US20050196418A1 - Bioavailability and improved delivery of alkaline pharmaceutical drugs - Google Patents

Bioavailability and improved delivery of alkaline pharmaceutical drugs Download PDF

Info

Publication number
US20050196418A1
US20050196418A1 US11/050,434 US5043405A US2005196418A1 US 20050196418 A1 US20050196418 A1 US 20050196418A1 US 5043405 A US5043405 A US 5043405A US 2005196418 A1 US2005196418 A1 US 2005196418A1
Authority
US
United States
Prior art keywords
acid
composition
group
skin
hydroxyacid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/050,434
Inventor
Ruey Yu
Eugene Van Scott
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/792,273 external-priority patent/US20040214215A1/en
Application filed by Individual filed Critical Individual
Priority to US11/050,434 priority Critical patent/US20050196418A1/en
Publication of US20050196418A1 publication Critical patent/US20050196418A1/en
Priority to PCT/US2006/003917 priority patent/WO2006084174A2/en
Abandoned legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542Carboxylic acids, e.g. a fatty acid or an amino acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365Hydroxycarboxylic acids; Ketocarboxylic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41Amines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/06Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/02Preparations for care of the skin for chemically bleaching or whitening the skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00Manicure or pedicure preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/006Antidandruff preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00Preparations for affecting hair growth

Definitions

  • Embodiments of the invention relate to a process of making and the use of topical compositions including a molecular complex formed between an alkaline pharmaceutical drug and at least one selected from a hydroxyacid, a polyhydroxy acid, related acid, a lactone, or combinations thereof.
  • the compositions provide improved bioavailability and improved delivery of the drug into the cutaneous tissues.
  • the alkaline pharmaceutical drugs preferably are organic compounds that contain at least one amino, imino and/or guanido group in the molecules.
  • the hydroxyacids, polyhydroxy acids, related acids, or lactones preferably include organic carboxylic acids having at least one hydroxyl group in the molecules and having a molecular weight of between about 50 to about 1000.
  • the molecular complex thus formed is optimally bioavailable for topical treatment of skin and nail diseases.
  • Transdermal delivery systems are a convenient and effective alternative for the administration of many types of medications, because the agents are delivered directly into the blood stream, avoiding first-pass metabolism in the liver, so that drug delivery is continuous and sustained. Transdermal delivery also provides a sustained and consistent delivery of medication, avoiding peaks and valleys in blood levels which are often associated with oral dosage forms. Thus, using transdermal delivery, one can administer lower doses of drug to achieve the same therapeutic effect compared to oral administration, reducing or eliminating dose-dependent side effects.
  • the skin which has protective layers designed to prevent penetration of foreign matter, must be sufficiently penetrated to provide the active agent to the desired site or for absorption into the bloodstream.
  • Skin is a complex organ system, consisting of multiple layers.
  • the uppermost, or “stratum corneum,” layer of skin consists of non-living material derived primarily from the terminal differentiation of epidermal keratinocytes, and provides a protective barrier for the underlying components of skin.
  • the epidermis contains a number of cell types, although keratinocytes are the major cell type.
  • Dermal fibroblasts are embedded within a matrix comprised of collagen, elastin, proteoglycans, and other extracellular matrix molecules. Blood capillaries are found in the dermis, but the epidermis is non-vascular.
  • the drug itself must be suitable for administration.
  • the size of a drug molecule, its charge, polarity, and pH are factors that contribute to the ability of the agent to penetrate the skin to the desired site or to blood vessels for systemic distribution.
  • the carrier enabling the transdermal delivery of the drug has similar constraints.
  • Transdermal patch devices which provide a controlled, continuous administration of a therapeutic agent through the skin are known as the art. Such devices, for example, are disclosed in U.S. Pat. Nos. 4,627,429; 4,784,857; 5,662,925; 5,788,983; and 6,113,940. These devices typically contain a therapeutic agent impermeable barrier layer that defines the outer surface of the device, and a permeable skin attaching membrane, such as an adhesive layer, sealed to the barrier layer in such a way as to create a reservoir between them in which the therapeutic agent is placed. Although such devices may be satisfactory for their intended purpose, they have been found to be irritating to the wearer of the patch, provide minimized control of drug delivery through the skin, are slower to prepare, do not allow for customized formulation, are not easily produced, and are not cost-effective.
  • chemical enhancers are compounds that are administered along with the drug (or in some cases the skin may be pretreated with a chemical enhancer) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin.
  • chemical penetration enhancers are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum.
  • the permeability of many therapeutic agents with diverse physicochemical characteristics may be enhanced using these chemical enhancement means.
  • salts have the advantage of better water solubility, which is important for oral administration, and in many cases also the advantage of better stability.
  • a further advantage is that active substance salts often are more easily crystallized, or it is anyway only the active substance salt which is crystalline at room temperature. This is the reason why many active substances are manufactured and available only in the form of their salts.
  • chlorhexidine is commonly used as a salt of dihydrochloride, diacetate and di-D-gluconate.
  • Erythromycin is commonly used as a salt of ethylsuccinate, acistrate, estolate, glucoheptonate, lactobionate, propionate and stearate.
  • the active substance salts are unsuitable since due to their higher polarity they are not capable of penetrating the lipophile barrier of the stratum corneum in the quantities required for the therapeutic purpose. Thus, it is necessary to transform active substance salts into their free base in order to utilize them in transdermal systems. Processes of making a topical composition comprising molecular complexes of these drugs with other vehicles for optimal bioavailability and improved delivery into the cutaneous tissues has not previously been described.
  • U.S. Pat. No. 5,877,212 discloses molecular complexes and sustained release formulations containing complexes formed between alpha hydroxyacids and related acids on the one hand, and a complexing agent on the other hand.
  • the complexing agents include organic amino compounds in free base form having one or more other functional groups with unshared electrons such as hydroxyl, carbonyl, amido, ester, and alkoxy groups.
  • the molecular complex provides for controlled release of the alpha hydroxyacid or related acid into the skin.
  • compositions and delivery systems to administer alkaline pharmaceutical drugs through the skin. It also a feature of an embodiment of the invention to provide methods of making the compositions, as well as methods of administering the compositions to a patient in need thereof.
  • a topical composition including a molecular complex formed between an alkaline pharmaceutical drug and at least one compound selected from a hydroxyacid, a polyhydroxy acid, a related acid, lactone forms of these acids, or combinations thereof.
  • a method of forming a molecular complex between an alkaline pharmaceutical drug and at least one of a hydroxyacid, polyhydroxyacid, related acid, and lactone involves dissolving the alkaline pharmaceutical drug salt and an alkali in an appropriate medium to form a free base of the pharmaceutical drug, and then separating the free base from the medium.
  • the method further includes adding at least one of a hydroxyacid, polyhydroxyacid, related acid, and lactone to the free base in a reaction medium to form a molecular complex.
  • a method of administering an alkaline pharmaceutical drug to a patient in need thereof comprising topically applying a molecular complex formed between an alkaline pharmaceutical drug and at least one compound selected from a hydroxyacid, a polyhydroxy acid, related acid, a lactone, or combinations thereof.
  • the molecular complex includes a therapeutically effective amount of the alkaline pharmaceutical drug.
  • Embodiments of the invention are not limited to the particular methodology, protocols, and reagents described in the preferred embodiments, as these may vary. It also is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of any embodiment of the present invention.
  • a reference to “an alkaline pharmaceutical drug” includes a plurality of such drugs
  • a reference to “a hydroxacid” is a reference to one or more hydroxyacids and equivalents thereof known to those skilled in the art, and so forth.
  • pharmaceutically effective amount is used herein to denote a quantity of pharmaceutical that is known to be effective to achieve the desired and known result of the drug.
  • the actual amount contained in the molecular complex likely will vary from the pharmaceutically effective amount, since some of the drug may not completely penetrate the skin together with the complex.
  • those skilled in the art are capable of determining the pharmaceutically acceptable amount of alkaline pharmaceutical drugs described herein, and to use the requisite amount in the molecular complex so that the pharmaceutically acceptable amount is delivered to the subject in need thereof.
  • related acid denotes a hydroxyacid in which the hydroxyl group is at any carbon position other than the alpha position, or the hydroxyl group is replaced by a keto group, or other miscellaneous organic hydroxycarboxylic acids that are not readily represented by a generic structure.
  • this group of compounds may be subdivided into (1) alpha ketoacids, (2) miscellaneous compounds, and (3) oligomers and polymers of hydroxyacids. These groups are set out in more detail below.
  • the stratum corneum consists of keratin-enriched corneocytes that are embedded in a lipid matrix and are resistant to penetration by ionic compounds or large molecules having a molecular weight of 800 or larger.
  • Most alkaline pharmaceutical drugs are available in the form of a salt with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid because the free base is chemically unstable due to air oxidation of the amino, imino and/or guanido group of the molecule, and these drugs when oxidized typically become discolored and topically unappealing.
  • the pharmaceutical drug When such inorganic salts are incorporated into a topical formulation, the pharmaceutical drug usually exists as a positively charged cation and cannot penetrate, or only partially penetrates the stratum corneum of the skin. The reason is believed to be due to the fact that the inorganic acids used for stabilization and isolation of the drug are strong acids and the drug molecule is fully ionized by such strong acids. The drug as a fully ionized cation is not in bioavailable form, and its topical effect is variable and inconsistent at best, and often is completely ineffective.
  • an inorganic salt of an alkaline pharmaceutical drug is reacted with equimolar amounts of an inorganic alkali such as sodium hydroxide or ammonium hydroxide to generate the free base of the drug.
  • an inorganic alkali such as sodium hydroxide or ammonium hydroxide
  • the free base of the drug then is reacted with an organic hydroxyacid, polyhydroxy acid, related acid, lactone, or combinations thereof, to form a molecular complex.
  • molecular complex as used throughout this description to define the formation of a molecular complex between an alkaline pharmaceutical drug and the hydroxyacid, or polyhydroxy acid, related acid, or lactone denotes a complex based on three attracting forces. These three attracting forces in increasing strength are: (a) dipolar/dipolar; (b) dipolar/ionic; and (c) ionic/ionic. The dipolar attracting forces are created between the hydroxyl groups of: (i) the hydroxyacid or polyhydroxy acid or related acid, or lactone; and (ii) the amino, imino and/or guanido group of an alkaline drug due to unshared electrons of the oxygen and nitrogen atoms, and the hydrogen atoms through hydrogen bonds.
  • the ionic attracting forces are created between the carboxyl group of the hydroxyacid or polyhydroxy acid, or related acid, or lactone on the one hand, and the protonated amino, imino or guanido group of an alkaline drug on the other hand.
  • the drug molecules having a dipolar/dipolar attracting force When a composition containing the above molecular complex is topically applied to the skin, the drug molecules having a dipolar/dipolar attracting force will penetrate the skin first, followed by the drug molecules having dipolar/ionic attracting forces.
  • the drug molecules having the ionic/ionic attracting forces are typically in salt form and therefore are not generally bioavailable for penetration into the skin.
  • the ionic drug molecule will become non-ionic because the cation is converted to a free base due to the dissociation equilibrium shift (Henderson-Hasselbalch Equation).
  • Henderson-Hasselbalch Equation dissociation equilibrium shift
  • most drug molecules become bioavailable in the molecular complex with a hydroxyacid or polyhydroxy acid, or related acid, or lactone.
  • the molar ratio of an alkaline drug to a hydroxyacid or polyhydroxy acid or related acid or lactone preferably ranges from about 1:0.1 to about 1:40, with a preferred range of from about 1:0.5 to about 1:5.
  • the formation of a molecular complex is more than or beyond the neutralization reaction between an alkali and an acid because the extra functional group(s), e.g., hydroxyl group(s), participate in the formation of molecular complex through intermolecular attracting forces.
  • alkaline pharmaceutical drugs that have amino, imino and/or quanido groups can form a molecular complex with hydroxyacids or polyhydroxy acids or related acids to provide a compound with improved bioavailabilty and improved delivery into the skin and nail plate.
  • alkaline pharmaceutical drug denotes a pharmaceutical agent or substance that is alkaline in its native form with pH above 7.0 when in solution or with ability to form a salt with an inorganic acid.
  • the alkaline pharmaceutical drugs are organic compounds that contain at least one amino, imino, guanidine, imidazole, pyrrolidine, or other heterocyclic group containing at least one nitrogen atom in the molecules.
  • alkaline pharmaceutical drugs include but are not limited to acebutolol, acetohydroxamic acid, actiq, acyclovir, albuterol, allopurinol, alloxanthine, alprazolam, alprenolol, amiloride, amantadine, aminacrine, amiodarone, amitriptyline, amorolfine, amodiaquin, amocarzine, amoxapine, amphetamine, atenolol, atropine, bemegride, benzocaine, bepridil, benztropine, bupivacaine, bupropion, burimamide, brompheniramine, butoconazole, caffeine, carbamazepine, chlordiazepoxide, chloroquine, chlorpheniramine, chlorpromazine, cimetidine, clonidine, cocaine, codeine, cyclizine, chlorhexidine, citalopram, clemas
  • Additional representative alkaline pharmaceutical drugs include the following: abacavir, adefovir dipivoxil, adenosine, alfuzosin, almotriptan, amlodipine, anagrelide, anastrozole, apomorphine, aprepitant, aripiprazole, atazanavir, atomoxetine, azathioprine, azelastine, azithromycin, benazepril, bendroflumethiazide, benzonatate, brimonidine, buprenorphine, butenafine, cabergoline, candesartan cilexetil, cefditoren pivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine, cevimeline, cilostazol, cinacalcet, ciprofloxacin, cladribine, clarithromycin, clomiphene, clopidogre
  • alkaline pharmaceutical drugs also are known by their trade names: abacavir, adefovir dipivoxil (Hepsera), adenosine (Adenocard), alfuzosin (Uroxatral), almotriptan (Axert), amlodipine, anagrelide (Agrylin), anastrozole (Arimidex), apomorphine (Apokyn), aprepitant (Emend), aripiprazole (Abilify), atazanavir (Reyataz), atomoxetine (Strattera), azathioprine (Azasan), azelastine (Astelin), azithromycin (Zithromax), benazepril (Lotensin), bendroflumethiazide, benzonatate (Tessalon), brimonidine (Alphagan), buprenorphine (Buprenex), butenafine (Mentax), ca
  • Suitable hydroxyacids may be divided into the following groups.
  • AHAs Alpha-Hydroxyacids
  • AHAs are organic carboxylic acids having one hydroxyl group attached directly to the alpha position of the aliphatic or alicyclic carbon atom, but not to a benzene or other aromatic ring. On a broader scope, AHAs may include those acids that have additional carboxyl groups.
  • the AHAs may be divided into three subgroups: (a) alkyl AHAs; (b) aralkyl AHAs; and (c) polycarboxyl AHAs.
  • the side chain radicals attached to the alpha carbon are hydrogen atoms or simple hydrocarbons called alkyl groups.
  • the generic structure may be represented as follows: R 1 R 2 C(OH)COOH where R 1 and R 2 may be independently H or alkyl group.
  • the alkyl AHAs may exist as stereoisomers as D, L and DL or R, S and RS forms when R 1 and R 2 are not identical.
  • the alkyl groups preferably are non-aromatic radicals such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl and stearyl.
  • Representative alkyl AHAs can be selected from the group consisting of 2-hydroxyethanoic acid (glycolic acid), 2-hydroxypropanoic acid (lactic acid), 2-methyl-2-hydroxypropanoic acid (methyllactic acid), 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid, 2-hydroxyeicosanoic acid (alpha hydroxyarachidonic acid), 2-hydroxytetraeicosanoic acid (cerebronic acid), 2-hydroxytetraeicosenoic acid (alpha hydroxynervonic acid), and mixtures thereof.
  • 2-hydroxyethanoic acid glycolic acid
  • 2-hydroxypropanoic acid lactic acid
  • 2-methyl-2-hydroxypropanoic acid methyllactic acid
  • 2-hydroxybutanoic acid 2-hydroxypentanoic acid
  • 2-hydroxyhexanoic acid 2-hydroxyheptanoic acid
  • Aralkyl AHAs include AHA having aralkyl groups, where aralkyl is an abbreviation for aryl plus alkyl.
  • An aralkyl AHA is formed when a phenyl group or other aromatic ring is attached to the alpha carbon of the alkyl AHA.
  • the generic structure is shown as follows. R 1 R 2 C(OH)COOH where R 1 and R 2 may be independently H, aryl or aralkyl group.
  • the aralkyl AHAs may exist as stereoisomers as D, L and DL or R, S and RS forms when R 1 and R 2 are not identical.
  • the aryl group preferably includes at least one aromatic radical such as phenyl, diphenyl, biphenyl and naphthyl.
  • the aralkyl group preferably includes at least one aromatic radical and one non-aromatic radical such as a phenylmethyl(benzyl), phenylethyl, phenylpropyl, diphenylmethyl, diphenylethyl, biphenylmethyl and naphthylmethyl group.
  • the hydroxyl group is attached to the non-aromatic alpha carbon atom.
  • Suitable aralkyl AHAs can be selected from the group 2-henyl-2-hydroxyethanoic acid (mandelic acid), 2,2-diphenyl-2-hydroxyethanoic acid (benzilic acid), 3-phenyl 2-hydroxypropanoic acid (3-phenyllactic acid), 2-phenyl-2-methyl-2-hydroxyethanoic acid (atrolactic acid, 2-phenyllactic acid), and mixtures thereof.
  • a polycarboxy AHA is an AHA that includes more than one carboxyl and/or hydroxyl group.
  • the generic structure may be shown as follows.
  • R 1 R 2 C(OH)COOH where R 1 and R 2 may be independently H, COOH, CH 2 COOH or CHOHCOOH.
  • Suitable polycarboxy AHAs may exist as stereoisomers as D, L and DL or R, S and RS forms when R 1 and R 2 are not identical.
  • Suitable polycarboxy AHAs can be selected from the group 2-hydroxypropane-1,3-dioic acid (tartronic acid), 2-hydroxybutane-1,4-dioic acid (malic acid), 2,3-dihydroxybutane-1,4-dioic acid (tartaric acid), 2-hydroxy-2-carboxypentane-1,5-dioic acid (citric acid), isocitric acid, and mixtures thereof.
  • BHAs Beta-Hydroxyacids
  • BHAs are organic carboxylic acids having one hydroxyl group attached to the beta position of aliphatic carbon atom.
  • the generic structure of a BHA typically is represented by the following formula: R 1 R 2 C(OH)CHR 3 COOH where R 1 , R 2 , R 3 may be H, alkyl, aryl or aralkyl group.
  • the BHA may exist as stereoisomers as D, L and DL or R, S and RS forms when R 1 and R 2 are not identical or R 3 is not H.
  • Suitable BHAs for use in the present invention can be selected from the group 3-hydroxypropanoic acid ( ⁇ -hydroxypropanoic acid), 3-hydroxybutanoic acid ( ⁇ -hydroxybutanoic acid), 3-hydroxypentanoic acid, 3-hydroxy-2-phenylpropanoic acid (tropic acid), and mixtures and combinations thereof.
  • salicylic acid is not a BHA because both the hydroxyl and carboxyl groups are attached directly to an aromatic benzene ring, and the chemical name is 2-hydroxybenzoic acid.
  • PHAs are organic carboxylic acids having multiple hydroxyl groups in addition to the alpha-hydroxyl group.
  • the PHAs typically exist in the lactone form, such as gluconolactone from gluconic acid.
  • Many PHAs are derived from carbohydrates and are important carbohydrate intermediates and metabolites. PHAs may be divided into three groups: (a) aldonic acid; (b) aldaric acid; and (c) alduronic acid.
  • aldonic acid When a common carbohydrate such as glucose, also called aldose, is oxidized at carbon one position from aldehyde to carboxyl group, the product is called aldonic acid, or more specifically gluconic acid.
  • the aldonic acid usually has multiple hydroxyl groups.
  • the generic structure for aldonic acids is provided by the following formula. R(CHOH) n CHOHCOOH where R is usually H or alkyl group; and n is an integer from 1-6.
  • the aldonic acids may exist as stereoisomers as D, L and DL, or R, S and RS forms. Many aldonic acids form intramolecular lactones by the removal of one mole of water between the carboxyl group and one hydroxyl group.
  • aldonic acids can be selected from the group 2,3-dihydroxypropanoic acid (glyceric acid), 2,3,4-trihydroxybutanoic acids (stereoisomers; erythronic acid and erythronolactone, threonic acid and threonolactone), 2,3,4,5-tetrahydroxypentanoic acids (stereoisomers; ribonic acid and ribonolactone, arabinoic acid and arabinolactone, xylonic acid and xylonolactone, lyxonic acid and lyxonolactone), 2,3,4,5,6-pentahydroxyhexanoic acids (stereoisomers; allonic acid and allonolactone, altronic acid and altronolactone, gluconic acid and gluconolactone, mannoic acid and mannolactone, gulonic acid and gulonolactone, idonic acid and idonolactone, galactonic acid and galactonolactone,
  • Aldaric acid typically has multiple hydroxyl groups attached to the carbon chain surrounded by two carboxyl groups.
  • Many aldaric acids exist as lactones, such as glucarolactone.
  • the generic structure is represented by the following formula: HOOC(CHOH) n CHOHCOOH where n is an integer from 1-4.
  • the aldaric acids may exist as stereoisomers as D, L and DL, or R, S and RS forms.
  • Many aldaric acids form intramolecular lactones by the removal of one mole of water between one carboxyl group and one hydroxyl group.
  • aldaric acids can be selected from the group consisting of 2,3-dihydroxybutane-1,4-dioic acids (stereoisomers; erythraric acid and threaric acid, also known as tartaric acid), 2,3,4-trihydroxypentane-1,5-dioic acids (stereoisomers; ribaric acid and ribarolactone, arabaric acid and arabarolactone, xylaric acid and xylarolactone, lyxaric acid and lyxarolactone), 2,3,4,5-tetrahydroxyhexane-1,6-dioic acids (stereoisomers; allaric acid and allarolactone, altraric acid and altrarolactone, glucaric acid and glucarolactone, mannaric acid and mannarolactone, gularic acid and gularolactone, idaric acid and idarolactone, galactaric acid and galacta
  • Alduronic acid preferably is obtained from a carbohydrate, aldose, by oxidation of the terminal carbon to a carboxyl group, and the carbon one position remains as an aldehyde group, such as glucuronic acid from glucose. Similar to aldonic acid and aldaric acid, alduronic acid also has multiple hydroxyl groups attached to the carbon chain between two functional groups, one aldehyde and one carboxyl groups in this case. Many alduronic acids exist as lactones, such as glucuronolactone from glucuronic acid. The generic structure is represented by the following formula: HOOC(CHOH) n CHOHCHO where n is an integer from 1-4.
  • the alduronic acids may exist as stereoisomers as D, L and DL, or R, S and RS forms. Many alduronic acids can form intramolecular lactones by the removal of one mole of water between the carboxyl group and one hydroxyl group.
  • alduronic acids can be selected from the group consisting of erythruronic acid, threuronic acid, riburonic acid and riburonolactone, araburonic acid and araburonolactone, xyluronic acid and xyluronolactone, lyxuronic acid and lyxuronolactone, alluronic acid and alluronolactone, altruronic acid and altruronolactone, glucuronic acid and glucuronolactone, mannuronic acid and mannuronolactone, guluronic acid and guluronolactone, iduronic acid and iduronolactone, galacturonic acid and galacturonolactone, taluronic acid and taluronolactone, allohepturonic acid and allohepturonolactone, altrohepturonic acid and altrohepturonolactone, glucohepturonic acid and glucohepturonolac
  • ABAs are also known as bionic acids, and typically consist of one monosaccharide chemically linked through an ether bond to an aldonic acid.
  • the ABA also may be described as an oxidized form of a disaccharide or dimeric carbohydrate, such as lactobionic acid from lactose.
  • lactobionic acid from lactose.
  • the carbon at position one of the monosaccharide is chemically linked to a hydroxyl group at different position of the aldonic acid. Therefore, different ABAs or stereoisomers can be formed from two identical monosaccharides and aldonic acids. Similar to PHAs, ABAs have multiple hydroxyl groups attached to carbon chains.
  • ABAs may be represented by the following generic formula: H(CHOH) m (CHOR)(CHOH) n COOH where m and n are integers independently from 0-7, and R is a monosaccharide.
  • ABAs may exist as stereoisomers as D, L and DL, or R, S and RS forms, and can form intramolecular lactones by the removal of one mole of water between the carboxyl group and one hydroxyl group. Chemical structures of most ABAs are more complicated than the above generic formula. Accordingly, the ABAs useful in forming the molecular complex of the invention will be described by reference to their chemical names.
  • Suitable ABAs useful in embodiments of the invention may be selected from the group consisting of lactobionic acid and lactobionolactone from lactose, isolactobionic acid and isolactobionolactone from isolactose, maltobionic acid and maltobionolactone from maltose, isomaltobionic acid and isomaltobionolactone from isomaltose, cellobionic acid and cellobionolactone from cellobiose, gentiobionic acid and gentiobionolactone from gentiobiose, kojibionic acid and kojibionolactone from kojibiose, laminaribionic acid and laminaribionolactone from laminaribiose, melibionic acid and melibionolactone from melibiose, nigerobionic acid and nigerobionolactone from nigerose, rutinobionic acid and rutinobionolactone
  • Preferred hydroxacids, polyhydroxyacids, and lactones, or combinations thereof include glycolic acid, lactic acid, gluconic acid, gluconolactone, ribonic acid, ribonolactone, galactonic acid, galactonolactone, glucoheptonic acid, glucoheptonolactone, glucuronic acid, glucuronolactone, galacturonic acid, galacturonolactone, glucaric acid, glucarolactone, galactaric acid, galactarolactone, lactobionic acid and maltobionic acid.
  • the related acids are those hydroxyacids in which the hydroxyl group is at any carbon position other than the alpha position, or the hydroxyl group is replaced by a keto group, or other miscellaneous organic hydroxycarboxylic acids which are not readily represented by a generic structure.
  • this group of compounds is subdivided into (1) alpha ketoacids, (2) miscellaneous compounds, and (3) oligomers and polymers of hydroxyacids.
  • Ketoacids are related to hydroxyacids in that the hydroxyl group is replaced by the keto group.
  • the keto group can be at any position other than the terminal ends, the preferred one is an alpha ketoacid.
  • an alpha ketoacid is related to lactic acid in that the hydroxyl group of lactic acid is substituted by a keto group.
  • lactate dehydrogenase enzyme converts pyruvate to lactate and vice visa.
  • the ketoacids have been found to have similar therapeutic effects as that of alpha hydroxyacids.
  • alpha ketoacids may be represented as follows: (Ra)COCOOH wherein Ra is H, alkyl, aralkyl or aryl group of saturated or unsaturated, isomeric or non-isomeric, straight or branched chain or cyclic form, having 1 to 25 carbon atoms, and in addition Ra may carry F, Cl, Br, I, OH, CHO, COOH and alkoxyl group having 1 to 9 carbon atoms.
  • the typical alkyl, aralkyl, aryl and alkoxyl groups for Ra include methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl, stearyl, benzyl, phenyl, methoxyl and ethoxyl.
  • alpha ketoacids that may be useful for forming the molecular complex of the invention are listed below: 2-ketoethanoic acid (glyoxylic acid), 2-ketopropanoic acid (pyruvic acid), 2-phenyl-2-ketoethanoic acid (benzoylformic acid), 3-phenyl-2-ketopropanoic acid (phenylpyruvic acid), 2-ketobutanoic acid, 2-ketopentanoic acid, 2-ketohexanoic acid, 2-ketoheptanoic acid, 2-ketooctanoic acid and 2-ketododecanoic acid.
  • hydroxyacids have similar therapeutic effects as that of alpha hydroxyacids but their chemical structures are not readily represented by the foregoing generic structures. These compounds are listed as follows: agaricic acid, aleuritic acid, citramalic acid, glucosaminic acid, galactosaminic acid, 2-keto-gulonic acid and 2-keto-gulonolactone, mannosaminic acid, mevalonic acid and mevalonolactone, pantoic acid and pantolactone, quinic acid (1,3,4,5-tetrahydroxycyclohexanecarboxylic acid), piscidic acid (4-hydroxybenzyltartaric acid), ascorbic acid (3-oxo-L-gulofuranolactone), Isoascorbic acid (D-erythro-hex-2-enonic acidr-lactone), 2-hexulosonic acids (isomers; arabino-2-hexulosonicacid, xylo-2-hexulosonic acid, ribo-2-he
  • oligomers When two or more molecules of hydroxyacids either identical or non-identical are reacted chemically to each other, oligomers are formed.
  • the chemical bond is usually an ester bond formed from the carboxyl group of one monomer and the hydroxyl group of a second monomer by eliminating a water molecule.
  • oligomers consist of 2 to 10 monomers of hydroxyacids.
  • the oligomers may be cyclic or non-cyclic form or a mixture of the two.
  • the generic structure of oligomers of hydroxyacids may be described as follows.
  • AHA in each monomer may be identical or not identical.
  • glycolyl glycolate glycolyl lactate, lactyl lactate and lactyl glycolate.
  • oligomers of AHA are listed below: glycolyl glycolate, lactyl lactate, citryl citrate, glycoly citrate, citryl glycolate, lactyl citrate, citryl lactate, malyl malate, malyl glycolate, tartaryl tartrate, tartaryl glycolate, glycolyl tartrate, glycolyl glycoly glycolate, lactyl lactyl lactate, and other AHA oligomers. It is preferred that the molecular weight of the polymeric hydroxyacid be within the range of from about 50 to about 1000.
  • the molecular weight of the hydroxyacid, or polyhydroxyacid, or related acid, or lactone form thereof be within the range of from about 50 to about 1000. It is more preferred that the molecular weight be within the range of from about 60 to about 700, and most preferred within the range of from about 70 to about 500.
  • the molecular complex formed from an alkaline drug and a hydroxyacid or polyhydroxy acid has been found to provide optimal bioavailability for topical treatment of various dermatological indications.
  • a therapeutic molecular complex can also be formed between an alkaline drug and N-acetylamino acid.
  • Typical N-acetylamino acids are described in U.S. Pat. No. 6,159,485, the disclosure of which is incorporated by reference herein in its entirety.
  • Representative N-acetylamino acids include N-acetyl-L-proline, N-acetyl-L-glutamine, N-acetyl-L-cysteine and N-acetyl-glycine.
  • the molecular complex composition also may preferably contain other pharmaceutical or topical agents to further expand the utilities for maximal therapeutic efficacies, such as in combination with N-acetylamino sugars as disclosed in U.S. Pat. No. 6,159,485, the disclosure of which is incorporated by reference herein in its entirety.
  • Suitable pharmaceutical and other topical agents that may be incorporated into embodiments of the molecular complex compositions of the invention include: those that improve or eradicate age spots, keratoses and wrinkles; local analgesics and anesthetics; antiacne agents; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antidandruff agents; antidermatitis agents; antihistamine agents; antipruritic agents; antiemetics; antimotionsickness agents; antiinflammatory agents; antihyperkeratolytic agents; antiperspirants; antipsoriatic agents; antiseborrheic agents; hair conditioners and hair treatment agents; antiaging and antiwrinkle agents; sunblock and sunscreen agents; skin lightening agents; depigmenting agents; vitamins; corticosteroids; tanning agents; humectants; hormones; retinoids; gum disease or oral care agents; topical cardiovascular agents; corn, callus and wart removing agents; dipilating agents, and mixtures and combinations thereof.
  • aclovate acyclovir
  • acetylsalicylic acid adapalene
  • aluminum acetate aluminum chloride, aluminum hydroxide, aluminum chlorohydroxide
  • aminobenzoic acid PABA
  • aminocaproic acid aminosalicylic acid
  • anthralin aminosalicylic acid
  • ascorbic acid ascoryl palimate
  • azelaic acid bacitracin
  • bemegride beclomethasone dipropionate
  • benzophenone benzoyl peroxide
  • betamethasone dipropionate betamethasone valerate
  • calcipotriene camphor
  • capsaicin carbamide peroxide
  • chitosan chloroxylenol
  • ciclopirox clobetasol propionate
  • coal tar dehydroepiandrosterone
  • desoximetasone dexametamethasone
  • compositions comprising a molecular complex of preferred embodiments of the present invention are topically effective for the general care of skin, hair and nail; nasal, oral and vaginal mucosa.
  • the compositions are useful in a variety of methods, including: treatment, healing and prevention of cosmetic conditions and dermatological indications, as well as cosmetic and clinical signs of changes associated with intrinsic or extrinsic aging; the damages caused by extrinsic factors such as sunlight, air pollution, wind, cold, dampness, heat, chemicals, smoke, cigarette smoking, and radiations including electromagnetic radiations and ionizing radiations.
  • the compositions also are useful for reducing and soothing mucosa and skin erythema, inflammation or reaction caused by internal or external factors.
  • General cosmetic conditions and dermatological indications that can be treated using the molecular complexes of various embodiments of the invention include: disturbed keratinization, inflammation, defective syntheses of dermal components, and changes associated with intrinsic and extrinsic aging of skin, nail and hair.
  • Particular conditions and indications include: dryness or looseness of skin, nail and hair; xerosis; ichthyosis; palmar and plantar hyperkeratoses; uneven and rough surface of skin, nail and hair; dandruff; Darier's disease; lichen simplex chronicus; keratoses; acne; pseudofolliculitis barbae; dermatoses; eczema; psoriasis; pruritus; warts; herpes; age spots; lentigines; melasmas; blemished skin; hyperkeratoses; hyperpigmented or hypopigmented skin; abnormal or diminished syntheses of collagen, glycosaminoglycans, proteoglycans and elastin as well as diminished levels of such components in the dermis; stretch marks; skin lines; fine lines; wrinkles; thinning of skin, nail plate and hair; skin thickening due to elastosis of photoaging, loss or reduction of skin, nail and hair resili
  • Specific skin changes associated with aging include, but are not limited to, progressive thinning of skin, fragile skin, deepening of skin lines and fine lines, wrinkles including fine and coarse wrinkles, lusterless skin surface, coarse and uneven skin, loss of skin elasticity and recoilability, blemished and leathery skin, loss of skin lubricating substances, increased numbers of blotches and mottles, nodules, pre-cancerous lesions, pigmented spots and mottled skin, changes in qualities and quantities of collagen and elastic fibers, solar elastosis, decrease in collagen fibers, diminution in the number and diameter of elastic fibers in the papillary dermis, atrophy of the dermis, stretch marks, reduction in subcutaneous adipose tissue and deposition of abnormal elastic materials in the upper dermis, yellowing skin, telangiectatic skin and older-looking skin.
  • a particularly preferred process for forming the molecular complex of the invention includes dissolving an alkaline pharmaceutical drug (0.1 mole in salt form) together with a sufficient amount of water (e.g., about 50 ml given the amount of drug). After dissolution, about 5N sodium hydroxide (20 ml) can be added slowly with stirring while the reaction flask is cooled externally in an ice-water bath. The free base of the drug is formed instantly and is usually separated as a precipitate or an oily product. The precipitate then can be isolated by filtration and washed with water and dried. The oily product can be isolated and washed with water using a separatory funnel.
  • an alkaline pharmaceutical drug 0.1 mole in salt form
  • water e.g., about 50 ml given the amount of drug
  • the above free base drug (0.1 mole) isolated as a precipitate or oily liquid then preferably is suspended in water (e.g., about 50 ml) and a hydroxyacid or polyhydroxy acid is added with stirring.
  • water e.g., about 50 ml
  • other solvents such as ethanol, propylene glycol, butylene glycol, etc may be added to the water solution before or after the formation of the molecular complex.
  • the formation of the molecular complex is evidenced by a decrease of the pH, and the reaction is completed as shown by no more change in the pH.
  • the concentration of hydroxyacid or polyhydroxy acid or lactone may vary anywhere from about 0.1 to about 40 moles, preferably from about 0.5 to about 5 moles, per one mole of alkaline drug.
  • the final pH of a composition containing a molecular complex may range from about 2.0 to about 7.0, with a preferred pH within the range of from about 3.0 to about 5.0.
  • a pharmaceutical or other topical agent can be added directly or first dissolved in water or other solvent and then added into a composition containing a molecular complex of an embodiment of the invention.
  • Other forms of compositions such as a solution, lotion, cream, ointment, gel etc. for topical delivery of the molecular complex containing an alkaline drug and a hydroxyacid or polyhydroxy acid or lactone of the instant invention can readily be prepared or formulated by those skilled in the art, using the guidelines provided herein.
  • the concentration of the alkaline pharmaceutical drug may range anywhere from 0.01 to 99.9%, with preferred concentration of from about 0.1 to 50% and with more preferred concentration of from about 1 to 25% by weight of the total composition. Other advantageous concentration ranges provide a concentration of at least 3%, 4% or 5% of the alkaline pharmaceutical drug. Higher concentrations of an alkaline pharmaceutical drug in the ranges of 40%, 50%, 60% or more also can be employed, depending on the desired end use.
  • acceptable ranges of an alkaline pharmaceutical drug will be from about 1%, 2%, 3%, 4% or 5% at the minimum, to about 95% at maximum, and within that range will be ranges of from about 1% to about 5%, from about 5% to about 10%, from about 10% to about 20%, from about 20% to about 40%, from about 40% to about 60%, from about 60% to about 80%, from about 80% to about 95%. These weights are based on the weight of the total composition.
  • the concentration of the hydroxyacid, polyhydroxy acid, related acid, or lactone forms of these acids, or combinations thereof, may range from 0.01 to 99.9%.
  • Advantageous concentrations will comprise at least 0.2% hydroxyacid, and typically at least about 1% or 2% of hydroxyacid.
  • Other advantageous concentration ranges provide at least being at least 3%, 4% or 5% of a hydroxyacid.
  • Higher concentrations of a hydroxyacid in the ranges of 40%, 50%, 60% or more also can be employed.
  • typical ranges of a hydroxyacid will be from about 1%, 2%, 3%, 4% or 5% at the minimum to 99.9% at maximum, and within that range will be ranges of from about 5% to about 10%, from about 10% to about 20%, from about 20% to about 40%, from about 40% to about 60%, from about 60% to about 80%, from about 80% to about 99.9%. These weights are based on the weight of the total composition.
  • a topical composition of the instant invention may also be formulated in a gel form.
  • a typical gel composition can be prepared by the addition of a gelling agent such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammonium glycyrrhizate to a solution mixture containing the molecular complex.
  • the preferred concentration of the gelling agent may range from 0.1 to 4 percent by weight of the total composition.
  • a typical process to convert a pharmaceutical drug from its salt form to a free base form is described as follows.
  • Diphenhydramine hydrochloride 29 g (0.1 mole) was dissolved in water (50 ml) and 5N sodium hydroxide (20 ml) was slowly added to generate diphenhydramine as a free base as shown by the formation of oily precipitates and the change from pH 5.5 to 9.4.
  • Gluconolactone 18 g (0.1 mole) was added to form a molecular complex between the diphenhydramine free base and gluconic acid/gluconolactone as shown by the disappearance of the oily precipitates and the change from pH 9.4 to 7.4.
  • the formation of the molecular complex was completed as indicated by no more change in pH of the solution.
  • the solution thus obtained contained 0.1 mole diphenhydramine in molecular complex with 0.1 mole gluconic acid/gluconolactone.
  • This concentrated stock solution was used for various forms of topical formulations including oil-in-water creams, lotions, gels and solutions.
  • An alternative method of forming the molecular complex is to use ammonium hydroxide instead of sodium hydroxide as follows.
  • Diphenhydramine hydrochloride 29 g (0.1 mole) was dissolved in water 50 ml and concentrated ammonium hydroxide 6.9 ml (0.1 mole) was slowly added to generate diphenhydramine as a free base as shown by the formation of oily precipitates and the change from pH 5.5 to 8.0.
  • Gluconolactone 18 g (0.1 mole) was added to form a molecular complex between diphenhydramine as a free base and gluconic acid/gluconolactone as shown by the disappearance of the oily precipitates and the change from pH 8.0 to 4.8.
  • the formation of the molecular complex was completed as indicated by no more change in pH of the solution.
  • the solution thus obtained contained 0.1 mole diphenhydramine in molecular complex with 0.1 mole gluconic acid/gluconolactone.
  • This concentrated stock solution was used for various forms of topical formulations including creams, lotions, gels and solutions.
  • the molar ratio of the molecular complex may be changed from 1:1 to 1:2 by carrying out the following.
  • Diphenhydramine hydrochloride 29 g (0.1 mole) was dissolved in water 50 ml and concentrated ammonium hydroxide 6.9 ml (0.1 mole) was slowly added to generate diphenhydramine as a free base as shown by the formation of oily precipitates and a change from pH 5.5 to 8.0.
  • Gluconolactone 36 g (0.2 mole) then was added to form a molecular complex between the diphenhydramine free base and gluconic acid/gluconolactone as shown by the disappearance of the oily precipitates and a change from pH 8.0 to 3.2.
  • the formation of molecular complex was completed as indicated by no more change in pH of the solution.
  • the solution thus obtained contained 0.1 mole diphenhydramine in molecular complex with 0.2 mole gluconic acid/gluconolactone.
  • This concentrated stock solution was used for various forms of topical formulations including solutions, lotions, creams and gels.
  • the molecular complex of diphenhydramine and gluconic acid/gluconolactone obtained from Example 1, 2, or 3 was mixed with an oil-in-water base to form a cream containing 2% of the active ingredient.
  • a male subject, age 71, with chronic nummular eczema and pruritic dry skin topically applied the above 2% diphenhydramine cream containing molecular complex 1:1 or 1:2 ratio to itchy skin areas of eczema and dry skin lesions.
  • hydrocortisone 17-valerate (0.2 g) first was dissolved in warm propylene glycol 20 ml, and the solution thus obtained was mixed with 79.8 g of molecular complex containing 2 g of diphenhydramine and 2.4 g of gluconic acid/gluconolactone in oil-in-water cream.
  • the synergetic composition thus formulated contained 0.2% hydrocortisone 17-valerate, 2% diphenhydramine, and 2.4% gluconic acid/gluconolactone, and was therapeutically effective for topical treatment to eradicate itch and improve eczematous or psoriatic lesions.
  • Clotrimazole is commercially available as a free base powder, but it is chemically unstable in a solution or formulation for shelf storage due to air oxidation.
  • a molecular complex composition can be formulated as follows.
  • Clotrimazole 2 g (5.8 mmole) was dissolved in 84 ml solution prepared from water (40 parts), ethanol (40 parts), and propylene glycol (20 parts), each part by volume.
  • Glycolic acid as a 70% aqueous solution, (14 ml-162.5 mmole) was added slowly to form a molecular complex as shown by a change of pH to 2.2.
  • the molecular complex thus prepared contained 2% clotrimazole and 12% glycolic acid in solution form.
  • Clotrimazole 2 g (5.8 mmole) was dissolved in 93 ml solution prepared from water (40 parts), ethanol (40 parts), and propylene glycol (20 parts), each part by volume.
  • N-Acetyl-L-proline 5 g (32 mmole) was added slowly to form a molecular complex as indicated by a change of pH to 3.8.
  • the solution thus obtained contained a molecular complex formed between 2% clotrimazole and 5% N-acetyl-L-proline that is useful for fungal infections of skin and nails.
  • Miconazole nitrate 47.9 g (0.1 mole) was suspended in water (50 ml), ethanol (50 ml), propylene glycol (50 ml), and 2N sodium hydroxide 50 ml (0.1 mole) was added with stirring. A sticky solid was initially formed from the mixture and became white crystals after continued stirring. The mixture was filtered and the white crystals were washed with water and dried. Miconazole free base, 42 g (0.1 mole) thus isolated, was used for the following preparation of a molecular complex.
  • micear free base 8.2 g (0.02 mole) was dissolved in ethanol (230 ml), propylene glycol (190 ml) and water (70.3 ml).
  • Glycolic acid 1.5 g (0.02 mole) was added with stirring to form a molecular complex as shown by decreasing pH of the mixture. The formation of the molecular complex was complete when the pH did not change further.
  • the antifungal formulation thus prepared with pH 4.4 contained 1.6% miconazole and 0.3% glycolic acid in a molecular complex.
  • Metronidazole 0.75 g (4.4 mmole) was dissolved in 89.25 ml solution prepared from water (40 parts), ethanol (40 parts) and propylene glycol (20 parts), each part by volume.
  • Gluconic acid 50% in water solution, 10 g (25.5 mmole) was added slowly to form a molecular complex between metronidazole and gluconic acid as shown by a change of pH to 2.4.
  • the composition thus obtained contained a molecular complex formed between 0.75% metronidazole and 5% gluconic acid, and was therapeutically effective for topical treatment of acne and rosacea.
  • a gel composition was readily formulated by the addition of a gelling agent such as methyl cellulose or ethyl cellulose at 1 to 2% concentration.
  • the composition thus obtained contained a molecular complex formed between 2.25% metronidazole and 15% gluconic acid, and was therapeutically effective for topical treatment of acne and rosacea.
  • a cream composition was readily formulated by mixing the above solution with 2 parts of an oil-in-water emulsion. The cream thus obtained contained 0.75% metronidazole in molecular complex with 5% gluconic acid.
  • Metronidazole 1.71 g (10 mmole) was dissolved in 94.5 ml solution prepared from water (40 parts), ethanol (40 parts), and propylene glycol (20 parts), each part by volume.
  • Glycolic acid 3.8 g (50 mmole) was added slowly to form a molecular complex between metronidazole and glycolic acid as shown by a change of pH to 2.3.
  • the composition thus obtained contained a molecular complex formed between 1.7% metronidazole and 3.8% glycolic acid, and was therapeutically effective for topical treatment of acne and rosacea.
  • a gel composition was readily formulated by the addition of a gelling agent such as methyl cellulose or ethyl cellulose at 1 to 2% concentration.
  • Fluoxetine hydrochloride known as Prozac is a psychotropic drug for oral administration. The following was a typical process to convert and incorporate an oral drug in capsule form into a composition comprising a molecular complex for topical administration.
  • Gluconolactone 178 mg (1 mmole) was added to the above stock solution (8 ml) that contained 155 mg (0.5 mmole) fluoxetine base.
  • the formation of a molecular complex between gluconolactone and fluoxetine was complete as shown by the pH of the solution changing from 9.1 to 4.6.
  • Propylene glycol (2 ml) was added.
  • the topical composition thus prepared had pH 4.6 and contained 1.55% fluoxetine (0.5 mmole) in molecular complex with 1.78% gluconolactone (1 mmole).
  • DL-lactic acid 88% in water 103 mg (90 mg lactic acid, 1 mmole) was added to the above stock solution 8 ml which contained 155 mg (0.5 mmole) fluoxetine base.
  • the formation of a molecular complex between lactic acid and fluoxetine was complete as shown by the pH of the solution changing from 9.1 to 3.8.
  • Propylene glycol (1 ml) was added and ethanol 1 ml was added to make the final volume to 10 ml.
  • the topical composition thus prepared had pH 3.8 and contained 1.55% fluoxetine (0.5 mmole) in molecular complex with 0.9% DL-lactic acid (1 mmole).
  • Tadalafil hydrochloride known as Cialis is an oral treatment for erectile dysfunction. The following was a typical process to convert and incorporate an oral drug in tablet form into a composition comprising molecular complex for topical administration.
  • Gluconolactone 178 mg (1 mmole) was added to the above stock solution (18 ml) that contained 97 mg (0.25 mmole) tadalafil base.
  • the formation of a molecular complex between gluconolactone and tadalafil was complete as shown by the pH of the solution changing from 10.8 to 4.7.
  • Propylene glycol (2 ml) was added.
  • the topical composition thus prepared had pH 4.7 and contained 0.485% tadalafil (0.25 mmole) in molecular complex with 0.89% gluconolactone (1 mmole).
  • glycolic acid 76 mg (1 mmole) was added to the above stock solution (18 ml) that contained 97 mg (0.25 mmole) tadalafil base.
  • the formation of a molecular complex between glycolic acid and tadalafil was complete as shown by the pH of the solution changing from 10.8 to 3.7.
  • Propylene glycol 2 ml was added.
  • the topical composition thus prepared had pH 3.7 and contained 0.485% tadalafil (0.25 mmole) in molecular complex with 0.38% glycolic acid (1 mmole).
  • Vardenafil hydrochloride known as Levitra is an oral treatment for erectile dysfunction.
  • the following was another example to convert and incorporate an oral drug in tablet form into a composition comprising molecular complex for topical administration.
  • DL-Lactic acid 88% in water 103 mg (90 mg lactic acid, 1 mmole) was added to the above stock solution (10 ml) that contained 145 mg (0.25 mmole) vardenafil base.
  • the formation of molecular complex between lactic acid and vardenafil was complete as shown by the pH of the solution changing from 8.9 to 3.9.
  • the topical composition thus prepared had pH 3.9 and contained 1.45% (0.25 mmole) vardenafil in molecular complex with 0.9% DL-lactic acid (1 mmole).
  • DL-mandelic acid 152 mg (1 mmole) was added to the above stock solution (10 ml) that contained 145 mg (0.25 mmole) vardenafil base.
  • the formation of molecular complex between mandelic acid and vardenafil was complete as shown by the pH of the solution changing from 8.9 to 4.0.
  • the topical composition thus prepared had pH 4.0 and contained 1.45% (0.25 mmole) vardenafil in molecular complex with 1.52% DL-mandelic acid (1 mmole).

Abstract

Embodiments of the invention relate to a composition, a process of making the composition, and to the use of the composition. The compositions include a molecular complex formed between an alkaline pharmaceutical drug and at least one selected from a hydroxyacid, a polyhydroxy acid, a related acid, a lactone, or combinations thereof. The compositions provide improved bioavailability and improved delivery of the drug into the cutaneous tissues.

Description

    RELATED APPLICATIONS
  • This application is a continuation-in-part of U.S. patent application Ser. No. 10/792,273, filed Mar. 4, 2004, and entitled: “Improved Bioavailability and Improved Delivery of Alkaline Pharmaceutical Drugs,” the disclosure of which is incorporated herein by reference in its entirety.
  • BACKGROUND OF THE INVENITON
  • 1. Field of the Invention
  • Embodiments of the invention relate to a process of making and the use of topical compositions including a molecular complex formed between an alkaline pharmaceutical drug and at least one selected from a hydroxyacid, a polyhydroxy acid, related acid, a lactone, or combinations thereof. The compositions provide improved bioavailability and improved delivery of the drug into the cutaneous tissues. The alkaline pharmaceutical drugs preferably are organic compounds that contain at least one amino, imino and/or guanido group in the molecules. The hydroxyacids, polyhydroxy acids, related acids, or lactones preferably include organic carboxylic acids having at least one hydroxyl group in the molecules and having a molecular weight of between about 50 to about 1000. The molecular complex thus formed is optimally bioavailable for topical treatment of skin and nail diseases.
  • 2. Description of Related Art
  • Transdermal delivery systems are a convenient and effective alternative for the administration of many types of medications, because the agents are delivered directly into the blood stream, avoiding first-pass metabolism in the liver, so that drug delivery is continuous and sustained. Transdermal delivery also provides a sustained and consistent delivery of medication, avoiding peaks and valleys in blood levels which are often associated with oral dosage forms. Thus, using transdermal delivery, one can administer lower doses of drug to achieve the same therapeutic effect compared to oral administration, reducing or eliminating dose-dependent side effects.
  • Preparing suitable formulations of medications is a challenging task. The skin, which has protective layers designed to prevent penetration of foreign matter, must be sufficiently penetrated to provide the active agent to the desired site or for absorption into the bloodstream. Skin is a complex organ system, consisting of multiple layers. The uppermost, or “stratum corneum,” layer of skin consists of non-living material derived primarily from the terminal differentiation of epidermal keratinocytes, and provides a protective barrier for the underlying components of skin. The epidermis contains a number of cell types, although keratinocytes are the major cell type. Dermal fibroblasts are embedded within a matrix comprised of collagen, elastin, proteoglycans, and other extracellular matrix molecules. Blood capillaries are found in the dermis, but the epidermis is non-vascular.
  • In addition, the drug itself must be suitable for administration. The size of a drug molecule, its charge, polarity, and pH are factors that contribute to the ability of the agent to penetrate the skin to the desired site or to blood vessels for systemic distribution. The carrier enabling the transdermal delivery of the drug has similar constraints.
  • Most transdermal delivery of pharmaceuticals involves incorporating the pharmaceutical into a carrier, such as a porous polymeric membrane, and using the membrane as a patch worn on the skin. Transdermal patch devices which provide a controlled, continuous administration of a therapeutic agent through the skin are known as the art. Such devices, for example, are disclosed in U.S. Pat. Nos. 4,627,429; 4,784,857; 5,662,925; 5,788,983; and 6,113,940. These devices typically contain a therapeutic agent impermeable barrier layer that defines the outer surface of the device, and a permeable skin attaching membrane, such as an adhesive layer, sealed to the barrier layer in such a way as to create a reservoir between them in which the therapeutic agent is placed. Although such devices may be satisfactory for their intended purpose, they have been found to be irritating to the wearer of the patch, provide minimized control of drug delivery through the skin, are slower to prepare, do not allow for customized formulation, are not easily produced, and are not cost-effective.
  • Numerous chemical agents have been studied as a means of increasing the rate at which a drug penetrates through the skin. As will be appreciated by those skilled in the art, chemical enhancers are compounds that are administered along with the drug (or in some cases the skin may be pretreated with a chemical enhancer) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin. Ideally, such chemical penetration enhancers are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum. The permeability of many therapeutic agents with diverse physicochemical characteristics may be enhanced using these chemical enhancement means. However, there are skin irritation and sensitization problems associated with high levels of certain enhancers.
  • Many medicinal active agents contain one or more basic nitrogen atoms in their molecule and can therefore be utilized in pharmaceutical preparations either as a free base or as a salt of the active substance base with an acid which is suitable for this purpose. Salts have the advantage of better water solubility, which is important for oral administration, and in many cases also the advantage of better stability. A further advantage is that active substance salts often are more easily crystallized, or it is anyway only the active substance salt which is crystalline at room temperature. This is the reason why many active substances are manufactured and available only in the form of their salts. For example, chlorhexidine is commonly used as a salt of dihydrochloride, diacetate and di-D-gluconate. Erythromycin is commonly used as a salt of ethylsuccinate, acistrate, estolate, glucoheptonate, lactobionate, propionate and stearate.
  • For transdermal administration, however, the active substance salts are unsuitable since due to their higher polarity they are not capable of penetrating the lipophile barrier of the stratum corneum in the quantities required for the therapeutic purpose. Thus, it is necessary to transform active substance salts into their free base in order to utilize them in transdermal systems. Processes of making a topical composition comprising molecular complexes of these drugs with other vehicles for optimal bioavailability and improved delivery into the cutaneous tissues has not previously been described.
  • An ideal process enables the release of the free base during the manufacture of the system in situ without the manufacturing process thereby becoming considerably more complicated than in the case of direct use of the free base. Such a process is described in EP 0 272 562. In this process, adhesives are used which themselves possess basic groups and are thereby themselves, as auxiliary bases, capable of liberating the free base. The disadvantage of this process is that the number of these functional basic groups in the adhesive is limited, and that for this reason only small amounts of active substance salts can be converted into their free bases.
  • Another process is described in U.S. Pat. No. 6,620,429 where active substance salt is converted with a basic alkaline metal salt, preferably a silicate, in an organic solvent. The transdermal systems described therein involve incorporation of the converted active substance into a polymer matrix patch after suspension in the organic solvent with the basic alkaline metal salt. There is a need to develop a more convenient approach to transdermal drug delivery, so that the active drug becomes more readily available and easily transportable through cutaneous tissue.
  • U.S. Pat. No. 5,877,212, the disclosure of which is incorporated by reference herein in its entirety, discloses molecular complexes and sustained release formulations containing complexes formed between alpha hydroxyacids and related acids on the one hand, and a complexing agent on the other hand. The complexing agents include organic amino compounds in free base form having one or more other functional groups with unshared electrons such as hydroxyl, carbonyl, amido, ester, and alkoxy groups. The molecular complex provides for controlled release of the alpha hydroxyacid or related acid into the skin.
  • The description herein of certain disadvantages of known materials, methods, systems, and apparatus is not intended to limit the scope of the invention. Indeed, various embodiments of the invention may include some or all of the known materials, methods, systems, and apparatus without suffering from the aforementioned disadvantages.
  • SUMMARY OF THE INVENTION
  • It is a feature of an embodiment of the invention to provide improved compositions and delivery systems to administer alkaline pharmaceutical drugs through the skin. It also a feature of an embodiment of the invention to provide methods of making the compositions, as well as methods of administering the compositions to a patient in need thereof.
  • In accordance with these and other features of various embodiments of the invention, there is provided a topical composition including a molecular complex formed between an alkaline pharmaceutical drug and at least one compound selected from a hydroxyacid, a polyhydroxy acid, a related acid, lactone forms of these acids, or combinations thereof.
  • In accordance with additional features of embodiments of the invention, there is provided a method of forming a molecular complex between an alkaline pharmaceutical drug and at least one of a hydroxyacid, polyhydroxyacid, related acid, and lactone. The method involves dissolving the alkaline pharmaceutical drug salt and an alkali in an appropriate medium to form a free base of the pharmaceutical drug, and then separating the free base from the medium. The method further includes adding at least one of a hydroxyacid, polyhydroxyacid, related acid, and lactone to the free base in a reaction medium to form a molecular complex.
  • In accordance with an additional feature of an embodiment of the invention, there is provided a method of administering an alkaline pharmaceutical drug to a patient in need thereof, comprising topically applying a molecular complex formed between an alkaline pharmaceutical drug and at least one compound selected from a hydroxyacid, a polyhydroxy acid, related acid, a lactone, or combinations thereof. The molecular complex includes a therapeutically effective amount of the alkaline pharmaceutical drug.
  • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • Embodiments of the invention are not limited to the particular methodology, protocols, and reagents described in the preferred embodiments, as these may vary. It also is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of any embodiment of the present invention.
  • Throughout this disclosure, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “an alkaline pharmaceutical drug” includes a plurality of such drugs, and a reference to “a hydroxacid” is a reference to one or more hydroxyacids and equivalents thereof known to those skilled in the art, and so forth.
  • Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are cited for the purpose of describing and disclosing the various molecules, drugs, delivery systems, and methodologies that are reported in the publications and that might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosures by virtue of prior invention.
  • The expression “pharmaceutically effective amount” is used herein to denote a quantity of pharmaceutical that is known to be effective to achieve the desired and known result of the drug. The actual amount contained in the molecular complex, likely will vary from the pharmaceutically effective amount, since some of the drug may not completely penetrate the skin together with the complex. Using the guidelines provided herein, those skilled in the art are capable of determining the pharmaceutically acceptable amount of alkaline pharmaceutical drugs described herein, and to use the requisite amount in the molecular complex so that the pharmaceutically acceptable amount is delivered to the subject in need thereof.
  • The expression “related acid” as it is used herein denotes a hydroxyacid in which the hydroxyl group is at any carbon position other than the alpha position, or the hydroxyl group is replaced by a keto group, or other miscellaneous organic hydroxycarboxylic acids that are not readily represented by a generic structure. For convenience this group of compounds may be subdivided into (1) alpha ketoacids, (2) miscellaneous compounds, and (3) oligomers and polymers of hydroxyacids. These groups are set out in more detail below.
  • In human skin, the stratum corneum consists of keratin-enriched corneocytes that are embedded in a lipid matrix and are resistant to penetration by ionic compounds or large molecules having a molecular weight of 800 or larger. Most alkaline pharmaceutical drugs are available in the form of a salt with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid because the free base is chemically unstable due to air oxidation of the amino, imino and/or guanido group of the molecule, and these drugs when oxidized typically become discolored and topically unappealing. When such inorganic salts are incorporated into a topical formulation, the pharmaceutical drug usually exists as a positively charged cation and cannot penetrate, or only partially penetrates the stratum corneum of the skin. The reason is believed to be due to the fact that the inorganic acids used for stabilization and isolation of the drug are strong acids and the drug molecule is fully ionized by such strong acids. The drug as a fully ionized cation is not in bioavailable form, and its topical effect is variable and inconsistent at best, and often is completely ineffective.
  • The present inventors have discovered a relatively simple process for converting the inorganic salt of an alkaline pharmaceutical drug into a molecular complex that provides the requisite bioavailability and therapeutic efficacy. In accordance with a preferred embodiment of the method, an inorganic salt of an alkaline pharmaceutical drug is reacted with equimolar amounts of an inorganic alkali such as sodium hydroxide or ammonium hydroxide to generate the free base of the drug. The free base of the drug then is reacted with an organic hydroxyacid, polyhydroxy acid, related acid, lactone, or combinations thereof, to form a molecular complex.
  • The expression “molecular complex” as used throughout this description to define the formation of a molecular complex between an alkaline pharmaceutical drug and the hydroxyacid, or polyhydroxy acid, related acid, or lactone denotes a complex based on three attracting forces. These three attracting forces in increasing strength are: (a) dipolar/dipolar; (b) dipolar/ionic; and (c) ionic/ionic. The dipolar attracting forces are created between the hydroxyl groups of: (i) the hydroxyacid or polyhydroxy acid or related acid, or lactone; and (ii) the amino, imino and/or guanido group of an alkaline drug due to unshared electrons of the oxygen and nitrogen atoms, and the hydrogen atoms through hydrogen bonds. The ionic attracting forces are created between the carboxyl group of the hydroxyacid or polyhydroxy acid, or related acid, or lactone on the one hand, and the protonated amino, imino or guanido group of an alkaline drug on the other hand.
  • When a composition containing the above molecular complex is topically applied to the skin, the drug molecules having a dipolar/dipolar attracting force will penetrate the skin first, followed by the drug molecules having dipolar/ionic attracting forces. The drug molecules having the ionic/ionic attracting forces are typically in salt form and therefore are not generally bioavailable for penetration into the skin. However, when more free base drug penetrates into the skin, the ionic drug molecule will become non-ionic because the cation is converted to a free base due to the dissociation equilibrium shift (Henderson-Hasselbalch Equation). Thus, most drug molecules become bioavailable in the molecular complex with a hydroxyacid or polyhydroxy acid, or related acid, or lactone.
  • The molar ratio of an alkaline drug to a hydroxyacid or polyhydroxy acid or related acid or lactone preferably ranges from about 1:0.1 to about 1:40, with a preferred range of from about 1:0.5 to about 1:5. The formation of a molecular complex is more than or beyond the neutralization reaction between an alkali and an acid because the extra functional group(s), e.g., hydroxyl group(s), participate in the formation of molecular complex through intermolecular attracting forces. The inventors believe that all alkaline pharmaceutical drugs that have amino, imino and/or quanido groups can form a molecular complex with hydroxyacids or polyhydroxy acids or related acids to provide a compound with improved bioavailabilty and improved delivery into the skin and nail plate.
  • The expression “alkaline pharmaceutical drug” denotes a pharmaceutical agent or substance that is alkaline in its native form with pH above 7.0 when in solution or with ability to form a salt with an inorganic acid. Typically, the alkaline pharmaceutical drugs are organic compounds that contain at least one amino, imino, guanidine, imidazole, pyrrolidine, or other heterocyclic group containing at least one nitrogen atom in the molecules. Representative alkaline pharmaceutical drugs include but are not limited to acebutolol, acetohydroxamic acid, actiq, acyclovir, albuterol, allopurinol, alloxanthine, alprazolam, alprenolol, amiloride, amantadine, aminacrine, amiodarone, amitriptyline, amorolfine, amodiaquin, amocarzine, amoxapine, amphetamine, atenolol, atropine, bemegride, benzocaine, bepridil, benztropine, bupivacaine, bupropion, burimamide, brompheniramine, butoconazole, caffeine, carbamazepine, chlordiazepoxide, chloroquine, chlorpheniramine, chlorpromazine, cimetidine, clonidine, cocaine, codeine, cyclizine, chlorhexidine, citalopram, clemastine, clindamycin, clioquinol, clotrimazole, clozapine, cromolyn, crotamiton, cyclizine, cycloserine, dexmedetomidine, dicyclomine, dihydromorphine, diphenhydramine, diphenoxylate, disopyramide, dobutamine, dopamine, dopamide, dopa esters, doxepin, doxylamine, dyclonine, desipramine, diazepam, dihydrocodeine, diphenoxylate, ephedrine, epinephrine, epinine, ergotamine, econazole, erythromycin, etidocaine, etomidate, fentanyl, fluoxetine, fluphenazine, flurazepam, fluvoxamine, guanethidine, guaifenesin, N-guanylhistamine, haloprogin, hydralazine, hypoxanthine, ichthammol, imiquimod, indomethacin, imipramine, irbesartan, isoetharine, isoproterenol, ketamine, ketanserin, ketoconazole, ketoprofen, kanamycin, labetalol, lamotrigine, lidocaine, lobeline, losartan, loxapine, lysergic diethylamide, mafenide, maprotiline, mecamylamine, meclizine, meclocycline, meperidine, mepivacaine, mescaline, metanephrine, metaproterenol, methadone, methoxamine, metiamide, metolazone, metronidazole, miconazole, midazolam, minocycline, minoxidil, mirtazapine, mupirocin metaraminol, methadone, methamphetamine, methyldopamide, methyldopa esters, metoprolol, mexiletine, molindone, morphine, moxonidine, 3,4-methylenedioxymethamphetamine, nadolol, naftifine, naloxone, nefazodone, neomycin, nifedipine, nystatin, nicotine, norepinephrine, octopamine, olanzapine, ondansetron, oxiconazole, oxotremorine, oxymetazoline, paroxetine, pentazocine, phencyclidine, pheniramine, phenmetrazine, phentolamine, phenylephrine, phenylpropanolamine, phenelzine, phenoxybenzamine, physostigmine, pilocarpine, pimozide, pipamazine, pirenzepine, podophyllin, podofilox, pramipexole, pramoxine, prenalterol, prilocalne, procaine, promethazine propionate, propranolol, protriptyline, pseudoephedrine, pyrethrin, pyrilamine pentazocine, phenylephrine, physostigmine, pilocarpine, pindolol, prazosin, procainamide, procaine, promazine, promethazine, propranolol, pseudoephedrine, pyrimethamine, quetiapine, quinethazone, quinidine, reserpine, risperidone, ritodrine, ropinirole, ropivacaine, salmeterol, scopolamine, selegiline, serotonin, sertindole, sertraline, sotalol, strychnine, sulconazole, sulfadiazine, sulfanilamide, tamsulosin, tazarotene, terbinafine, terconazole, terfenadine, tetracaine, tetracycline, tetrahydrozoline, theobromine, theophylline, thymol, timolol, tioconazole, tizanidine, tocainide, tolnaftate, tranylcypromine, trazodone, triamterene, triazolam, triflupromazine, tripelennamine, triprolidine, terbutaline, thioridazine, tyramine, tolazoline, xanthine, venlafaxine, verapamil and ziprasidone, and mixtures thereof.
  • Additional representative alkaline pharmaceutical drugs include the following: abacavir, adefovir dipivoxil, adenosine, alfuzosin, almotriptan, amlodipine, anagrelide, anastrozole, apomorphine, aprepitant, aripiprazole, atazanavir, atomoxetine, azathioprine, azelastine, azithromycin, benazepril, bendroflumethiazide, benzonatate, brimonidine, buprenorphine, butenafine, cabergoline, candesartan cilexetil, cefditoren pivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine, cevimeline, cilostazol, cinacalcet, ciprofloxacin, cladribine, clarithromycin, clomiphene, clopidogrel, cyclobenzaprine, cytarabine, dacarbazine, dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine, delavirdine, desloratadine, desmopressin, dexmethylphenidate, dexrazoxane, dextroamphetamine, didanosine, diltiazem, dipyridamole, dofetilide, dolasetron, donepezil, dorzolamide, doxorubicin, doxycycline, duloxetine, eflornithine, eletriptan, emtricitabine, enalapril, epirubicin, eptifibatide, escitalopram, esmolol, esomeprazole, estazolam, famciclovir, famotidine, felodipine, fexofenadine, flecainide, fluconazole, flucytosine, formoterol, galantamine, gatifloxacin, gefitinib, gemcitabine, gemifloxacin, haloperidol, homatropine, hydrochlorothiazide, hydromorphone, hyoscyamine, idarubicin, imatinib, indinavir, irinotecan, itraconazole, ketotifen, lamivudine, lansoprazole, letrozole, leuprolide, levalbuterol, levofloxacin, linezolid, loperamide, mebendazole, memantine, mercaptopurine, metformin, methylphenidate, midodrine, miglustat, mitoxantrone, moexiprilat, moxifloxacin, nalbuphine, nalmefene, nelfinavir, nevirapine, nicardipine, nimodipine, nisoldipine, nizatidine, octreotide, ofloxacin, olmesartan medoxomil, olopatadine, omeprazole, oxybutynin, oxycodone, palonosetron, pemoline, penciclovir, pentostatin, pentoxifylline, pergolide, pioglitazone, procarbazine, propafenone, propoxyphene, quinapril, quinupristin, ribavirin, rifampin, rifapentine, rifaximin, riluzole, rimantadine, rivastigmine, rizatriptan, sibutramine, sildenafil, streptomycin, sulfamethoxazole, sulfisoxazole, tadalafil, tegaserol, telithromycin, telmisartan, temozolomide, tenofovir disoproxil, terazosin, thiabendazole, thiothixene, tiagabine, tinidazole, tirofiban, tobramycin, tolterodine, tramadol, trimethoprim, trimipramine, tromethamine, vardenafil, voriconazole, zafirlukast, zaleplon, zolmitriptan and zolpidem.
  • Many of the above alkaline pharmaceutical drugs also are known by their trade names: abacavir, adefovir dipivoxil (Hepsera), adenosine (Adenocard), alfuzosin (Uroxatral), almotriptan (Axert), amlodipine, anagrelide (Agrylin), anastrozole (Arimidex), apomorphine (Apokyn), aprepitant (Emend), aripiprazole (Abilify), atazanavir (Reyataz), atomoxetine (Strattera), azathioprine (Azasan), azelastine (Astelin), azithromycin (Zithromax), benazepril (Lotensin), bendroflumethiazide, benzonatate (Tessalon), brimonidine (Alphagan), buprenorphine (Buprenex), butenafine (Mentax), cabergoline (Dostinex), candesartan cilexetil (Atacand), cefditoren pivoxil (Spectracef), cefepime (Maxipime), cefpodoxime proxetil (Vantin), celecoxib (Celebrex), cetirizine (Zyrtec), cevimeline (Evoxac), cilostazol (Pletal), cinacalcet (Sensipar), ciprofloxacin (Ciloxan), ciprofloxacin (Cipro), cladribine (Leustatin), clarithromycin (Biaxin), clomiphene (Clomid), clomiphene (Serophene), clopidogrel (Plavix), cyclobenzaprine (Flexeril), cytarabine (Depocyt), dacarbazine (DTIC), dalfopristin, dapsone, daptomycin (Cubicin), daunorubicin (Cerubidine), deferoxamine (Desferal), delavirdine (Rescriptor), desloratadine (Clarinex), desmopressin (DDAVP), dexmethylphenidate (Focalin), dexrazoxane (Zinecard), dextroamphetamine (Dextrostat), didanosine (Videx), diltiazem (Cardizem), diltiazem (Tiazac), dipyridamole (Persantine), dofetilide (Tikosyn), dolasetron (Anzemet), donepezil (Aricept), dorzolamide, doxorubicin (Adriamycin), doxorubicin (Doxil), doxycycline (Adoxa), doxycycline (Periostat), duloxetine, duloxetine (Cymbalta), eflornithine (Vaniqa), eletriptan (Relpax), emtricitabine (Emtriva), enalapril (Lexxel), epirubicin (Ellence), eptifibatide (Integrilin), escitalopram (Lexpro), esmolol (Brevibloc), esomeprazole (Nexium), estazolam (Prosom), famciclovir (Famvir), famotidine (Pepcid), felodipine (Plendil), fexofenadine (Allegra), flecainide (Tambocor), fluconazole (Diflucan), flucytosine (Ancobon), formoterol (Foradil), galantamine (Reminyl), gatifloxacin (Tequin), gatifloxacin (Zymar), gefitinib (Iressa), gemcitabine (Gemzar), gemifloxacin (Factive), haloperidol (Haldol), homatropine, hydrochlorothiazide (HCT), hydromorphone (Dilaudid), hyoscyamine (Nulev), idarubicin (Idamycin), imatinib (Gleevec), indinavir (Crixivan), irinotecan (Camptosar), itraconazole (Sporanox), ketotifen (Zaditor), lamivudine, lansoprazole (Prevacid), letrozole (Femara), leuprolide (Viadur), levalbuterol (Xopenex), levofloxacin (Levaquin), levofloxacin (Quixin), linezolid (Zyvox), loperamide (Imodium), mebendazole (Vermox), memantine (Namenda), mercaptopurine (Purinethol), metformin (Fortamet), methylphenidate (Concerta), methylphenidate (Metadate), methylphenidate (Ritalin), midodrine (Proamatine), miglustat (Zavesca), mitoxantrone (Novantrone), moexiprilat (Uniretic), moxifloxacin (Avelox), moxifloxacin (Vigamox), nalbuphine (Nubain), nalmefene (Revex), nelfinavir (Viracept), nevirapine (Viramune), nicardipine (Cardene), nimodipine (Nimotop), nisoldipine (Sular), nizatidine (Axid), octreotide (Sandostatin), ofloxacin (Floxin), olmesartan medoxomil (Benicar), olopatadine (Patanol), omeprazole (Prilosec), omeprazole (Zegerid), oxybutynin (Ditropan), oxybutynin (Oxytrol), oxycodone, palonosetron (Aloxi), pemoline (Cylert), penciclovir (Denavir), pentostatin (Nipent), pentoxifylline (Trental), pergolide (Permax), pioglitazone (Actos), procarbazine (Matulane), propafenone (Rythmol), propoxyphene (Darvon), quinapril (Accupril), quinupristin, ribavirin (Copegus), rifampin (Rifadin), rifapentine (Priftin), rifaximin (Xifaxan), riluzole (Rilutek), rimantadine (Flumadine), rivastigmine (Exelon), rizatriptan (Maxalt), sibutramine (Meridia), sildenafil (Viagra), streptomycin, sulfamethoxazole, sulfisoxazole, tadalafil (Cialis), tegaserol (Zelnorm), telithromycin (Ketek), telmisartan (Micarbis), temozolomide (Temodar), tenofovir disoproxil (Viread), terazosin (Hytrin), thiabendazole (Mintezol), thiothixene, tiagabine (Gabitril), tinidazole (Tindamax), tirofiban (Aggrastat), tobramycin (Tobi), tolterodine (Detrol), tramadol (Ultracet), trimethoprim, trimipramine (Surmontil), tromethamine, vardenafil (Levitra), voriconazole (Vfend), zafirlukast (Accolate), zaleplon (Sonata), zolmitriptan (Zomig) and zolpidem (Ambien). One or any combination of the above-mentioned alkaline pharmaceutical drugs can be used in various embodiments of the invention.
  • The hydroxyacids and polyhydroxy acids useful in forming a molecular complex with the alkaline pharmaceutical drugs mentioned previously are described in more detail below. Suitable hydroxyacids may be divided into the following groups.
  • 1. Alpha-Hydroxyacids (AHAs)
  • AHAs are organic carboxylic acids having one hydroxyl group attached directly to the alpha position of the aliphatic or alicyclic carbon atom, but not to a benzene or other aromatic ring. On a broader scope, AHAs may include those acids that have additional carboxyl groups. The AHAs may be divided into three subgroups: (a) alkyl AHAs; (b) aralkyl AHAs; and (c) polycarboxyl AHAs.
  • (a) Alkyl AHAs
  • The side chain radicals attached to the alpha carbon are hydrogen atoms or simple hydrocarbons called alkyl groups. The generic structure may be represented as follows:
    R1R2C(OH)COOH
    where R1 and R2 may be independently H or alkyl group. The alkyl AHAs may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical. The alkyl groups preferably are non-aromatic radicals such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl and stearyl.
  • Representative alkyl AHAs can be selected from the group consisting of 2-hydroxyethanoic acid (glycolic acid), 2-hydroxypropanoic acid (lactic acid), 2-methyl-2-hydroxypropanoic acid (methyllactic acid), 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid, 2-hydroxyeicosanoic acid (alpha hydroxyarachidonic acid), 2-hydroxytetraeicosanoic acid (cerebronic acid), 2-hydroxytetraeicosenoic acid (alpha hydroxynervonic acid), and mixtures thereof.
  • (b) Aralkyl AHAs
  • Aralkyl AHAs include AHA having aralkyl groups, where aralkyl is an abbreviation for aryl plus alkyl. An aralkyl AHA is formed when a phenyl group or other aromatic ring is attached to the alpha carbon of the alkyl AHA. The generic structure is shown as follows.
    R1R2C(OH)COOH
    where R1 and R2 may be independently H, aryl or aralkyl group. The aralkyl AHAs may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical. The aryl group preferably includes at least one aromatic radical such as phenyl, diphenyl, biphenyl and naphthyl. The aralkyl group preferably includes at least one aromatic radical and one non-aromatic radical such as a phenylmethyl(benzyl), phenylethyl, phenylpropyl, diphenylmethyl, diphenylethyl, biphenylmethyl and naphthylmethyl group. In any case, the hydroxyl group is attached to the non-aromatic alpha carbon atom.
  • Suitable aralkyl AHAs can be selected from the group 2-henyl-2-hydroxyethanoic acid (mandelic acid), 2,2-diphenyl-2-hydroxyethanoic acid (benzilic acid), 3-phenyl 2-hydroxypropanoic acid (3-phenyllactic acid), 2-phenyl-2-methyl-2-hydroxyethanoic acid (atrolactic acid, 2-phenyllactic acid), and mixtures thereof.
  • (c) Polycarboxy AHAs
  • A polycarboxy AHA is an AHA that includes more than one carboxyl and/or hydroxyl group. The generic structure may be shown as follows.
    R1R2C(OH)COOH
    where R1 and R2 may be independently H, COOH, CH2COOH or CHOHCOOH. Suitable polycarboxy AHAs may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical.
  • Suitable polycarboxy AHAs can be selected from the group 2-hydroxypropane-1,3-dioic acid (tartronic acid), 2-hydroxybutane-1,4-dioic acid (malic acid), 2,3-dihydroxybutane-1,4-dioic acid (tartaric acid), 2-hydroxy-2-carboxypentane-1,5-dioic acid (citric acid), isocitric acid, and mixtures thereof.
  • 2. Beta-Hydroxyacids (BHAs)
  • BHAs are organic carboxylic acids having one hydroxyl group attached to the beta position of aliphatic carbon atom. The generic structure of a BHA typically is represented by the following formula:
    R1R2C(OH)CHR3COOH
    where R1, R2, R3 may be H, alkyl, aryl or aralkyl group. The BHA may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical or R3 is not H.
  • Suitable BHAs for use in the present invention can be selected from the group 3-hydroxypropanoic acid (β-hydroxypropanoic acid), 3-hydroxybutanoic acid (β-hydroxybutanoic acid), 3-hydroxypentanoic acid, 3-hydroxy-2-phenylpropanoic acid (tropic acid), and mixtures and combinations thereof. For clarification, salicylic acid is not a BHA because both the hydroxyl and carboxyl groups are attached directly to an aromatic benzene ring, and the chemical name is 2-hydroxybenzoic acid.
  • 3. Polyhydroxy Acids (PHAs)
  • PHAs are organic carboxylic acids having multiple hydroxyl groups in addition to the alpha-hydroxyl group. The PHAs typically exist in the lactone form, such as gluconolactone from gluconic acid. Many PHAs are derived from carbohydrates and are important carbohydrate intermediates and metabolites. PHAs may be divided into three groups: (a) aldonic acid; (b) aldaric acid; and (c) alduronic acid.
  • (a) Aldonic Acid
  • When a common carbohydrate such as glucose, also called aldose, is oxidized at carbon one position from aldehyde to carboxyl group, the product is called aldonic acid, or more specifically gluconic acid. The aldonic acid usually has multiple hydroxyl groups. The generic structure for aldonic acids is provided by the following formula.
    R(CHOH)nCHOHCOOH
    where R is usually H or alkyl group; and n is an integer from 1-6. The aldonic acids may exist as stereoisomers as D, L and DL, or R, S and RS forms. Many aldonic acids form intramolecular lactones by the removal of one mole of water between the carboxyl group and one hydroxyl group.
  • Representative aldonic acids can be selected from the group 2,3-dihydroxypropanoic acid (glyceric acid), 2,3,4-trihydroxybutanoic acids (stereoisomers; erythronic acid and erythronolactone, threonic acid and threonolactone), 2,3,4,5-tetrahydroxypentanoic acids (stereoisomers; ribonic acid and ribonolactone, arabinoic acid and arabinolactone, xylonic acid and xylonolactone, lyxonic acid and lyxonolactone), 2,3,4,5,6-pentahydroxyhexanoic acids (stereoisomers; allonic acid and allonolactone, altronic acid and altronolactone, gluconic acid and gluconolactone, mannoic acid and mannolactone, gulonic acid and gulonolactone, idonic acid and idonolactone, galactonic acid and galactonolactone, talonic acid and talonolactone), 2,3,4,5,6,7-hexahydroxyheptanoic acids (stereoisomers; alloheptonic acid and alloheptonolactone, altroheptonic acid and altroheptonolactone, glucoheptonic acid and glucoheptonolactone, mannoheptonic acid and mannoheptonolactone, guloheptonic acid and guloheptonolactone, idoheptonic acid and idoheptonolactone, galactoheptonic acid and galactoheptonolactone, taloheptonic acid and taloheptonolactone), and mixtures thereof.
  • (b) Aldaric Acid
  • Aldaric acid typically has multiple hydroxyl groups attached to the carbon chain surrounded by two carboxyl groups. Many aldaric acids exist as lactones, such as glucarolactone. The generic structure is represented by the following formula:
    HOOC(CHOH)nCHOHCOOH
    where n is an integer from 1-4. The aldaric acids may exist as stereoisomers as D, L and DL, or R, S and RS forms. Many aldaric acids form intramolecular lactones by the removal of one mole of water between one carboxyl group and one hydroxyl group.
  • Representative aldaric acids can be selected from the group consisting of 2,3-dihydroxybutane-1,4-dioic acids (stereoisomers; erythraric acid and threaric acid, also known as tartaric acid), 2,3,4-trihydroxypentane-1,5-dioic acids (stereoisomers; ribaric acid and ribarolactone, arabaric acid and arabarolactone, xylaric acid and xylarolactone, lyxaric acid and lyxarolactone), 2,3,4,5-tetrahydroxyhexane-1,6-dioic acids (stereoisomers; allaric acid and allarolactone, altraric acid and altrarolactone, glucaric acid and glucarolactone, mannaric acid and mannarolactone, gularic acid and gularolactone, idaric acid and idarolactone, galactaric acid and galactarolactone, talaric acid and talarolactone), 2,3,4,5,6-pentahydroxyheptane-1,7-dioic acids (stereoisomers; alloheptaric acid and alloheptarolactone, altroheptaric acid and altroheptarolactone, glucoheptaric acid and glucoheptarolactone, mannoheptaric acid and mannoheptarolactone, guloheptaric acid and guloheptarolactone, idoheptaric acid and idoheptarolactone, galactoheptaric acid and galactoheptarolactone, taloheptaric acid and taloheptarolactone), and mixtures thereof.
  • (c) Alduronic Acid
  • Alduronic acid preferably is obtained from a carbohydrate, aldose, by oxidation of the terminal carbon to a carboxyl group, and the carbon one position remains as an aldehyde group, such as glucuronic acid from glucose. Similar to aldonic acid and aldaric acid, alduronic acid also has multiple hydroxyl groups attached to the carbon chain between two functional groups, one aldehyde and one carboxyl groups in this case. Many alduronic acids exist as lactones, such as glucuronolactone from glucuronic acid. The generic structure is represented by the following formula:
    HOOC(CHOH)nCHOHCHO
    where n is an integer from 1-4. The alduronic acids may exist as stereoisomers as D, L and DL, or R, S and RS forms. Many alduronic acids can form intramolecular lactones by the removal of one mole of water between the carboxyl group and one hydroxyl group.
  • Representative alduronic acids can be selected from the group consisting of erythruronic acid, threuronic acid, riburonic acid and riburonolactone, araburonic acid and araburonolactone, xyluronic acid and xyluronolactone, lyxuronic acid and lyxuronolactone, alluronic acid and alluronolactone, altruronic acid and altruronolactone, glucuronic acid and glucuronolactone, mannuronic acid and mannuronolactone, guluronic acid and guluronolactone, iduronic acid and iduronolactone, galacturonic acid and galacturonolactone, taluronic acid and taluronolactone, allohepturonic acid and allohepturonolactone, altrohepturonic acid and altrohepturonolactone, glucohepturonic acid and glucohepturonolactone, mannohepturonic acid and mannohepturonolactone, gulohepturonic acid and gulohepturonolactone, idohepturonic acid and idohepturonolactone, galactohepturonic acid and galactohepturonolactone, talohepturonic acid and talohepturonolactone, and mixtures thereof.
  • 4. Aldobionic Acids (ABAs)
  • ABAs are also known as bionic acids, and typically consist of one monosaccharide chemically linked through an ether bond to an aldonic acid. The ABA also may be described as an oxidized form of a disaccharide or dimeric carbohydrate, such as lactobionic acid from lactose. In most ABAs, the carbon at position one of the monosaccharide is chemically linked to a hydroxyl group at different position of the aldonic acid. Therefore, different ABAs or stereoisomers can be formed from two identical monosaccharides and aldonic acids. Similar to PHAs, ABAs have multiple hydroxyl groups attached to carbon chains. ABAs may be represented by the following generic formula:
    H(CHOH)m(CHOR)(CHOH)nCOOH
    where m and n are integers independently from 0-7, and R is a monosaccharide. ABAs may exist as stereoisomers as D, L and DL, or R, S and RS forms, and can form intramolecular lactones by the removal of one mole of water between the carboxyl group and one hydroxyl group. Chemical structures of most ABAs are more complicated than the above generic formula. Accordingly, the ABAs useful in forming the molecular complex of the invention will be described by reference to their chemical names.
  • Suitable ABAs useful in embodiments of the invention may be selected from the group consisting of lactobionic acid and lactobionolactone from lactose, isolactobionic acid and isolactobionolactone from isolactose, maltobionic acid and maltobionolactone from maltose, isomaltobionic acid and isomaltobionolactone from isomaltose, cellobionic acid and cellobionolactone from cellobiose, gentiobionic acid and gentiobionolactone from gentiobiose, kojibionic acid and kojibionolactone from kojibiose, laminaribionic acid and laminaribionolactone from laminaribiose, melibionic acid and melibionolactone from melibiose, nigerobionic acid and nigerobionolactone from nigerose, rutinobionic acid and rutinobionolactone from rutinose, sophorobionic acid and sophorobionolactone from sophorose, and mixtures thereof.
  • Preferred hydroxacids, polyhydroxyacids, and lactones, or combinations thereof, include glycolic acid, lactic acid, gluconic acid, gluconolactone, ribonic acid, ribonolactone, galactonic acid, galactonolactone, glucoheptonic acid, glucoheptonolactone, glucuronic acid, glucuronolactone, galacturonic acid, galacturonolactone, glucaric acid, glucarolactone, galactaric acid, galactarolactone, lactobionic acid and maltobionic acid.
  • 5. Related Acids
  • The related acids are those hydroxyacids in which the hydroxyl group is at any carbon position other than the alpha position, or the hydroxyl group is replaced by a keto group, or other miscellaneous organic hydroxycarboxylic acids which are not readily represented by a generic structure. For convenience this group of compounds is subdivided into (1) alpha ketoacids, (2) miscellaneous compounds, and (3) oligomers and polymers of hydroxyacids.
  • (a) Alpha Ketoacids
  • Ketoacids are related to hydroxyacids in that the hydroxyl group is replaced by the keto group. Although the keto group can be at any position other than the terminal ends, the preferred one is an alpha ketoacid. For example pyruvic acid, an alpha ketoacid is related to lactic acid in that the hydroxyl group of lactic acid is substituted by a keto group. In the skin, lactate dehydrogenase enzyme converts pyruvate to lactate and vice visa. The ketoacids have been found to have similar therapeutic effects as that of alpha hydroxyacids. The generic structure of alpha ketoacids may be represented as follows:
    (Ra)COCOOH
    wherein Ra is H, alkyl, aralkyl or aryl group of saturated or unsaturated, isomeric or non-isomeric, straight or branched chain or cyclic form, having 1 to 25 carbon atoms, and in addition Ra may carry F, Cl, Br, I, OH, CHO, COOH and alkoxyl group having 1 to 9 carbon atoms. The typical alkyl, aralkyl, aryl and alkoxyl groups for Ra include methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl, stearyl, benzyl, phenyl, methoxyl and ethoxyl.
  • Representative alpha ketoacids that may be useful for forming the molecular complex of the invention are listed below: 2-ketoethanoic acid (glyoxylic acid), 2-ketopropanoic acid (pyruvic acid), 2-phenyl-2-ketoethanoic acid (benzoylformic acid), 3-phenyl-2-ketopropanoic acid (phenylpyruvic acid), 2-ketobutanoic acid, 2-ketopentanoic acid, 2-ketohexanoic acid, 2-ketoheptanoic acid, 2-ketooctanoic acid and 2-ketododecanoic acid.
  • (b) Miscellaneous Hydroxyacids
  • These hydroxyacids have similar therapeutic effects as that of alpha hydroxyacids but their chemical structures are not readily represented by the foregoing generic structures. These compounds are listed as follows: agaricic acid, aleuritic acid, citramalic acid, glucosaminic acid, galactosaminic acid, 2-keto-gulonic acid and 2-keto-gulonolactone, mannosaminic acid, mevalonic acid and mevalonolactone, pantoic acid and pantolactone, quinic acid (1,3,4,5-tetrahydroxycyclohexanecarboxylic acid), piscidic acid (4-hydroxybenzyltartaric acid), ascorbic acid (3-oxo-L-gulofuranolactone), Isoascorbic acid (D-erythro-hex-2-enonic acidr-lactone), 2-hexulosonic acids (isomers; arabino-2-hexulosonicacid, xylo-2-hexulosonic acid, ribo-2-hexulosonic acid, lyxo-2-hexulosonic acid), 5-hexulosonic acids (isomers; arabino-5-hexulosonic acid, xylo-5-hexulosonic acid, ribo-5-hexulosonic acid, lyxo-5-hexulosonic acid).
  • (c) Oligomers of Hydroxyacids
  • When two or more molecules of hydroxyacids either identical or non-identical are reacted chemically to each other, oligomers are formed. The chemical bond is usually an ester bond formed from the carboxyl group of one monomer and the hydroxyl group of a second monomer by eliminating a water molecule. In general, oligomers consist of 2 to 10 monomers of hydroxyacids. The oligomers may be cyclic or non-cyclic form or a mixture of the two. The generic structure of oligomers of hydroxyacids may be described as follows.
    (AHA)m-n(H2O)
    wherein, AHA is a hydroxyacid described above, m=2-10, with a preferred number of 2-4, and n=m−1. AHA in each monomer may be identical or not identical. For example, glycolyl glycolate, glycolyl lactate, lactyl lactate and lactyl glycolate. Representative oligomers of AHA are listed below: glycolyl glycolate, lactyl lactate, citryl citrate, glycoly citrate, citryl glycolate, lactyl citrate, citryl lactate, malyl malate, malyl glycolate, tartaryl tartrate, tartaryl glycolate, glycolyl tartrate, glycolyl glycoly glycolate, lactyl lactyl lactate, and other AHA oligomers. It is preferred that the molecular weight of the polymeric hydroxyacid be within the range of from about 50 to about 1000.
  • Because the molecular complex should be effective in permitting the release of the drug through the skin, it is preferred that the molecular weight of the hydroxyacid, or polyhydroxyacid, or related acid, or lactone form thereof be within the range of from about 50 to about 1000. It is more preferred that the molecular weight be within the range of from about 60 to about 700, and most preferred within the range of from about 70 to about 500.
  • The molecular complex formed from an alkaline drug and a hydroxyacid or polyhydroxy acid has been found to provide optimal bioavailability for topical treatment of various dermatological indications. A therapeutic molecular complex can also be formed between an alkaline drug and N-acetylamino acid. Typical N-acetylamino acids are described in U.S. Pat. No. 6,159,485, the disclosure of which is incorporated by reference herein in its entirety. Representative N-acetylamino acids include N-acetyl-L-proline, N-acetyl-L-glutamine, N-acetyl-L-cysteine and N-acetyl-glycine.
  • The beneficial effects of forming the molecular complexes of various embodiments of the invention are readily apparent when considering, for example, that a 2% miconazole nitrate formulation is not therapeutically effective for topical treatment of fungal infections of nails. In contrast, a 1-2% miconazole molecular complex with glycolic acid has been found to be therapeutically effective for the topical treatment of nails with fungal infections. In a similar fashion, diphenhydramine hydrochloride (2% formulation) is not therapeutically effective for topical treatment of skin itch, but a 2% diphenhydramine molecular complex with gluconolactone has been found to be topically effective for eradication of skin itch. These unexpected and surprising results can be realized with molecular complexes of other alkaline pharmaceutical drugs.
  • The molecular complex composition also may preferably contain other pharmaceutical or topical agents to further expand the utilities for maximal therapeutic efficacies, such as in combination with N-acetylamino sugars as disclosed in U.S. Pat. No. 6,159,485, the disclosure of which is incorporated by reference herein in its entirety. Suitable pharmaceutical and other topical agents that may be incorporated into embodiments of the molecular complex compositions of the invention include: those that improve or eradicate age spots, keratoses and wrinkles; local analgesics and anesthetics; antiacne agents; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antidandruff agents; antidermatitis agents; antihistamine agents; antipruritic agents; antiemetics; antimotionsickness agents; antiinflammatory agents; antihyperkeratolytic agents; antiperspirants; antipsoriatic agents; antiseborrheic agents; hair conditioners and hair treatment agents; antiaging and antiwrinkle agents; sunblock and sunscreen agents; skin lightening agents; depigmenting agents; vitamins; corticosteroids; tanning agents; humectants; hormones; retinoids; gum disease or oral care agents; topical cardiovascular agents; corn, callus and wart removing agents; dipilating agents, and mixtures and combinations thereof.
  • Other useful pharmaceutical and other topical agents that can be included in embodiments of the molecular complex compositions of the invention include those selected from the group consisting of aclovate, acyclovir, acetylsalicylic acid, adapalene, aluminum acetate, aluminum chloride, aluminum hydroxide, aluminum chlorohydroxide, aminobenzoic acid (PABA), aminocaproic acid, aminosalicylic acid, anthralin, ascorbic acid, ascoryl palimate, azelaic acid, bacitracin, bemegride, beclomethasone dipropionate, benzophenone, benzoyl peroxide, betamethasone dipropionate, betamethasone valerate, calcipotriene, camphor, capsaicin, carbamide peroxide, chitosan, chloroxylenol, ciclopirox, clobetasol propionate, coal tar, dehydroepiandrosterone, desoximetasone, dexamethasone, estradiol, ethinyl estradiol, fluocinonide, fluocinolone acetonide, 5-fluorouracil, griseofulvin, hexylresorcinol, homosalate, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrogen peroxide, hydroquinone, hydroquinone monoether, hydroxyzine, ibuprofen, indomethacin, kojic acid, menthol, methyl nicotinate, methyl salicylate, monobenzone, naproxen, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate O, permethrin, phenol, piperonyl butoxide, povidone iodine, resorcinol, retinal, 13-cis retinoic acid, retinoic acid, retinol, retinyl acetate, retinyl palmitate, salicylamide, salicylic acid, selenium sulfide, shale tar, sulfur, triamcinolone diacetate, triamcinolone acetonide, triamcinolone hexacetonide, triclosan, undecylenic acid, urea, vitamin E acetate, wood tar, zinc pyrithione, N-acetyl-prolinamide, N-acetyl-lysine, N-acetyl-ornithine, N-acetyl-glucosamine, and mixtures thereof.
  • The present inventors also have discovered that compositions comprising a molecular complex of preferred embodiments of the present invention are topically effective for the general care of skin, hair and nail; nasal, oral and vaginal mucosa. The compositions are useful in a variety of methods, including: treatment, healing and prevention of cosmetic conditions and dermatological indications, as well as cosmetic and clinical signs of changes associated with intrinsic or extrinsic aging; the damages caused by extrinsic factors such as sunlight, air pollution, wind, cold, dampness, heat, chemicals, smoke, cigarette smoking, and radiations including electromagnetic radiations and ionizing radiations. The compositions also are useful for reducing and soothing mucosa and skin erythema, inflammation or reaction caused by internal or external factors.
  • General cosmetic conditions and dermatological indications that can be treated using the molecular complexes of various embodiments of the invention include: disturbed keratinization, inflammation, defective syntheses of dermal components, and changes associated with intrinsic and extrinsic aging of skin, nail and hair. Particular conditions and indications include: dryness or looseness of skin, nail and hair; xerosis; ichthyosis; palmar and plantar hyperkeratoses; uneven and rough surface of skin, nail and hair; dandruff; Darier's disease; lichen simplex chronicus; keratoses; acne; pseudofolliculitis barbae; dermatoses; eczema; psoriasis; pruritus; warts; herpes; age spots; lentigines; melasmas; blemished skin; hyperkeratoses; hyperpigmented or hypopigmented skin; abnormal or diminished syntheses of collagen, glycosaminoglycans, proteoglycans and elastin as well as diminished levels of such components in the dermis; stretch marks; skin lines; fine lines; wrinkles; thinning of skin, nail plate and hair; skin thickening due to elastosis of photoaging, loss or reduction of skin, nail and hair resiliency, elasticity and recoilability; lack of skin, nail and hair lubticants and luster; dull and older-looking skin, nail and hair; fragility and splitting of nail and hair, or used as to lighten the skin.
  • Specific skin changes associated with aging include, but are not limited to, progressive thinning of skin, fragile skin, deepening of skin lines and fine lines, wrinkles including fine and coarse wrinkles, lusterless skin surface, coarse and uneven skin, loss of skin elasticity and recoilability, blemished and leathery skin, loss of skin lubricating substances, increased numbers of blotches and mottles, nodules, pre-cancerous lesions, pigmented spots and mottled skin, changes in qualities and quantities of collagen and elastic fibers, solar elastosis, decrease in collagen fibers, diminution in the number and diameter of elastic fibers in the papillary dermis, atrophy of the dermis, stretch marks, reduction in subcutaneous adipose tissue and deposition of abnormal elastic materials in the upper dermis, yellowing skin, telangiectatic skin and older-looking skin.
  • A particularly preferred process for forming the molecular complex of the invention includes dissolving an alkaline pharmaceutical drug (0.1 mole in salt form) together with a sufficient amount of water (e.g., about 50 ml given the amount of drug). After dissolution, about 5N sodium hydroxide (20 ml) can be added slowly with stirring while the reaction flask is cooled externally in an ice-water bath. The free base of the drug is formed instantly and is usually separated as a precipitate or an oily product. The precipitate then can be isolated by filtration and washed with water and dried. The oily product can be isolated and washed with water using a separatory funnel.
  • To prepare a typical molecular complex composition, the above free base drug (0.1 mole) isolated as a precipitate or oily liquid then preferably is suspended in water (e.g., about 50 ml) and a hydroxyacid or polyhydroxy acid is added with stirring. Alternatively, other solvents such as ethanol, propylene glycol, butylene glycol, etc may be added to the water solution before or after the formation of the molecular complex. The formation of the molecular complex is evidenced by a decrease of the pH, and the reaction is completed as shown by no more change in the pH. The concentration of hydroxyacid or polyhydroxy acid or lactone may vary anywhere from about 0.1 to about 40 moles, preferably from about 0.5 to about 5 moles, per one mole of alkaline drug. The final pH of a composition containing a molecular complex may range from about 2.0 to about 7.0, with a preferred pH within the range of from about 3.0 to about 5.0.
  • To prepare a synergistic or synergetic composition, a pharmaceutical or other topical agent can be added directly or first dissolved in water or other solvent and then added into a composition containing a molecular complex of an embodiment of the invention. Other forms of compositions such as a solution, lotion, cream, ointment, gel etc. for topical delivery of the molecular complex containing an alkaline drug and a hydroxyacid or polyhydroxy acid or lactone of the instant invention can readily be prepared or formulated by those skilled in the art, using the guidelines provided herein.
  • The concentration of the alkaline pharmaceutical drug may range anywhere from 0.01 to 99.9%, with preferred concentration of from about 0.1 to 50% and with more preferred concentration of from about 1 to 25% by weight of the total composition. Other advantageous concentration ranges provide a concentration of at least 3%, 4% or 5% of the alkaline pharmaceutical drug. Higher concentrations of an alkaline pharmaceutical drug in the ranges of 40%, 50%, 60% or more also can be employed, depending on the desired end use. Thus, acceptable ranges of an alkaline pharmaceutical drug will be from about 1%, 2%, 3%, 4% or 5% at the minimum, to about 95% at maximum, and within that range will be ranges of from about 1% to about 5%, from about 5% to about 10%, from about 10% to about 20%, from about 20% to about 40%, from about 40% to about 60%, from about 60% to about 80%, from about 80% to about 95%. These weights are based on the weight of the total composition.
  • The concentration of the hydroxyacid, polyhydroxy acid, related acid, or lactone forms of these acids, or combinations thereof, (collectively referred to as “hydroxyacid” in this paragraph) may range from 0.01 to 99.9%. Advantageous concentrations will comprise at least 0.2% hydroxyacid, and typically at least about 1% or 2% of hydroxyacid. Other advantageous concentration ranges provide at least being at least 3%, 4% or 5% of a hydroxyacid. Higher concentrations of a hydroxyacid in the ranges of 40%, 50%, 60% or more also can be employed. Thus, typical ranges of a hydroxyacid will be from about 1%, 2%, 3%, 4% or 5% at the minimum to 99.9% at maximum, and within that range will be ranges of from about 5% to about 10%, from about 10% to about 20%, from about 20% to about 40%, from about 40% to about 60%, from about 60% to about 80%, from about 80% to about 99.9%. These weights are based on the weight of the total composition.
  • To prepare a topical composition in lotion, cream or ointment form, the above aqueous mixture containing the molecular complex preferably is mixed in a conventional manner with a commonly available lotion, cream or ointment base. A topical composition of the instant invention may also be formulated in a gel form. A typical gel composition can be prepared by the addition of a gelling agent such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammonium glycyrrhizate to a solution mixture containing the molecular complex. The preferred concentration of the gelling agent may range from 0.1 to 4 percent by weight of the total composition.
  • The following are illustrative examples of formulations and test results, and are not limiting. Therefore, any of the aforementioned alkaline drugs, hydroxyacids and polyhydroxy acids and lactones can be substituted according to the teachings of this invention in the following examples.
  • EXAMPLE 1
  • A typical process to convert a pharmaceutical drug from its salt form to a free base form is described as follows. Diphenhydramine hydrochloride 29 g (0.1 mole) was dissolved in water (50 ml) and 5N sodium hydroxide (20 ml) was slowly added to generate diphenhydramine as a free base as shown by the formation of oily precipitates and the change from pH 5.5 to 9.4. Gluconolactone 18 g (0.1 mole) was added to form a molecular complex between the diphenhydramine free base and gluconic acid/gluconolactone as shown by the disappearance of the oily precipitates and the change from pH 9.4 to 7.4. The formation of the molecular complex was completed as indicated by no more change in pH of the solution. The solution thus obtained contained 0.1 mole diphenhydramine in molecular complex with 0.1 mole gluconic acid/gluconolactone. This concentrated stock solution was used for various forms of topical formulations including oil-in-water creams, lotions, gels and solutions.
  • EXAMPLE 2
  • An alternative method of forming the molecular complex is to use ammonium hydroxide instead of sodium hydroxide as follows. Diphenhydramine hydrochloride 29 g (0.1 mole) was dissolved in water 50 ml and concentrated ammonium hydroxide 6.9 ml (0.1 mole) was slowly added to generate diphenhydramine as a free base as shown by the formation of oily precipitates and the change from pH 5.5 to 8.0. Gluconolactone 18 g (0.1 mole) was added to form a molecular complex between diphenhydramine as a free base and gluconic acid/gluconolactone as shown by the disappearance of the oily precipitates and the change from pH 8.0 to 4.8. The formation of the molecular complex was completed as indicated by no more change in pH of the solution. The solution thus obtained contained 0.1 mole diphenhydramine in molecular complex with 0.1 mole gluconic acid/gluconolactone. This concentrated stock solution was used for various forms of topical formulations including creams, lotions, gels and solutions.
  • EXAMPLE 3
  • The molar ratio of the molecular complex may be changed from 1:1 to 1:2 by carrying out the following. Diphenhydramine hydrochloride 29 g (0.1 mole) was dissolved in water 50 ml and concentrated ammonium hydroxide 6.9 ml (0.1 mole) was slowly added to generate diphenhydramine as a free base as shown by the formation of oily precipitates and a change from pH 5.5 to 8.0. Gluconolactone 36 g (0.2 mole) then was added to form a molecular complex between the diphenhydramine free base and gluconic acid/gluconolactone as shown by the disappearance of the oily precipitates and a change from pH 8.0 to 3.2. The formation of molecular complex was completed as indicated by no more change in pH of the solution. The solution thus obtained contained 0.1 mole diphenhydramine in molecular complex with 0.2 mole gluconic acid/gluconolactone. This concentrated stock solution was used for various forms of topical formulations including solutions, lotions, creams and gels.
  • EXAMPLE 4
  • The molecular complex of diphenhydramine and gluconic acid/gluconolactone obtained from Example 1, 2, or 3 was mixed with an oil-in-water base to form a cream containing 2% of the active ingredient. A male subject, age 71, with chronic nummular eczema and pruritic dry skin topically applied the above 2% diphenhydramine cream containing molecular complex 1:1 or 1:2 ratio to itchy skin areas of eczema and dry skin lesions. A few minutes after the topical application, the itch disappeared completely and the lesions remained free of itch for the next 8 hours.
  • EXAMPLE 5
  • For alternative treatment of eczema and other dermatoses, hydrocortisone 17-valerate (0.2 g) first was dissolved in warm propylene glycol 20 ml, and the solution thus obtained was mixed with 79.8 g of molecular complex containing 2 g of diphenhydramine and 2.4 g of gluconic acid/gluconolactone in oil-in-water cream. The synergetic composition thus formulated contained 0.2% hydrocortisone 17-valerate, 2% diphenhydramine, and 2.4% gluconic acid/gluconolactone, and was therapeutically effective for topical treatment to eradicate itch and improve eczematous or psoriatic lesions.
  • EXAMPLE 6
  • Clotrimazole is commercially available as a free base powder, but it is chemically unstable in a solution or formulation for shelf storage due to air oxidation. A molecular complex composition can be formulated as follows.
  • Clotrimazole 2 g (5.8 mmole) was dissolved in 84 ml solution prepared from water (40 parts), ethanol (40 parts), and propylene glycol (20 parts), each part by volume. Glycolic acid, as a 70% aqueous solution, (14 ml-162.5 mmole) was added slowly to form a molecular complex as shown by a change of pH to 2.2. The molecular complex thus prepared contained 2% clotrimazole and 12% glycolic acid in solution form.
  • A male subject, age 64, having fungal infections on the left great toe nail for several months topically applied the above molecular complex once daily on the infected nail plate. After 8 months of topical treatment, there was no clinical signs of fungal infections and the nail grew to the normal length. This result reveals that the molecular complex formed between clotrimazole and glycolic acid is therapeutically effective for topical treatment of fungal infections.
  • EXAMPLE 7
  • Clotrimazole 2 g (5.8 mmole) was dissolved in 93 ml solution prepared from water (40 parts), ethanol (40 parts), and propylene glycol (20 parts), each part by volume. N-Acetyl-L-proline 5 g (32 mmole) was added slowly to form a molecular complex as indicated by a change of pH to 3.8. The solution thus obtained contained a molecular complex formed between 2% clotrimazole and 5% N-acetyl-L-proline that is useful for fungal infections of skin and nails.
  • EXAMPLE 8
  • Miconazole nitrate 47.9 g (0.1 mole) was suspended in water (50 ml), ethanol (50 ml), propylene glycol (50 ml), and 2N sodium hydroxide 50 ml (0.1 mole) was added with stirring. A sticky solid was initially formed from the mixture and became white crystals after continued stirring. The mixture was filtered and the white crystals were washed with water and dried. Miconazole free base, 42 g (0.1 mole) thus isolated, was used for the following preparation of a molecular complex.
  • Miconazole free base 8.2 g (0.02 mole) was dissolved in ethanol (230 ml), propylene glycol (190 ml) and water (70.3 ml). Glycolic acid 1.5 g (0.02 mole) was added with stirring to form a molecular complex as shown by decreasing pH of the mixture. The formation of the molecular complex was complete when the pH did not change further. The antifungal formulation thus prepared with pH 4.4 contained 1.6% miconazole and 0.3% glycolic acid in a molecular complex.
  • EXAMPLE 9
  • Metronidazole 0.75 g (4.4 mmole) was dissolved in 89.25 ml solution prepared from water (40 parts), ethanol (40 parts) and propylene glycol (20 parts), each part by volume. Gluconic acid 50% in water solution, 10 g (25.5 mmole) was added slowly to form a molecular complex between metronidazole and gluconic acid as shown by a change of pH to 2.4. The composition thus obtained contained a molecular complex formed between 0.75% metronidazole and 5% gluconic acid, and was therapeutically effective for topical treatment of acne and rosacea. Alternatively, a gel composition was readily formulated by the addition of a gelling agent such as methyl cellulose or ethyl cellulose at 1 to 2% concentration.
  • EXAMPLE 10
  • Metronidazole 2.25 g (13.2 mmole) was dissolved in 67.8 ml solution prepared from water (40 parts), ethanol (40 parts), and propylene glycol (20 parts), each part by volume. Gluconic acid 50% in water solution 30 g (76.5 mmole) was added slowly to form a molecular complex between metronidazole and gluconic acid as shown by a change of pH to 2.1. The composition thus obtained contained a molecular complex formed between 2.25% metronidazole and 15% gluconic acid, and was therapeutically effective for topical treatment of acne and rosacea. Alternatively, a cream composition was readily formulated by mixing the above solution with 2 parts of an oil-in-water emulsion. The cream thus obtained contained 0.75% metronidazole in molecular complex with 5% gluconic acid.
  • EXAMPLE 11
  • Metronidazole 1.71 g (10 mmole) was dissolved in 94.5 ml solution prepared from water (40 parts), ethanol (40 parts), and propylene glycol (20 parts), each part by volume. Glycolic acid 3.8 g (50 mmole) was added slowly to form a molecular complex between metronidazole and glycolic acid as shown by a change of pH to 2.3. The composition thus obtained contained a molecular complex formed between 1.7% metronidazole and 3.8% glycolic acid, and was therapeutically effective for topical treatment of acne and rosacea. Alternatively, a gel composition was readily formulated by the addition of a gelling agent such as methyl cellulose or ethyl cellulose at 1 to 2% concentration.
  • EXAMPLE 12
  • Fluoxetine hydrochloride known as Prozac is a psychotropic drug for oral administration. The following was a typical process to convert and incorporate an oral drug in capsule form into a composition comprising a molecular complex for topical administration.
  • Fluoxetine hydrochloride (Prozac) powder 346 mg (1 mmole) from oral capsules, each containing 20 mg fluoxetine, was suspended in water 10 ml, and 1N sodium hydroxide 1 ml (1 mmole) was slowly added to generate fluoxetine free base. Ethanol (10 ml) was added to dissolve fluoxetine base, and the mixture was filtered. The filtrate containing fluoxetine base had pH 9.1. This filtrate (16 ml) was used as a stock solution for the preparation of topical compositions comprising molecular complex as follows.
  • Gluconolactone 178 mg (1 mmole) was added to the above stock solution (8 ml) that contained 155 mg (0.5 mmole) fluoxetine base. The formation of a molecular complex between gluconolactone and fluoxetine was complete as shown by the pH of the solution changing from 9.1 to 4.6. Propylene glycol (2 ml) was added. The topical composition thus prepared had pH 4.6 and contained 1.55% fluoxetine (0.5 mmole) in molecular complex with 1.78% gluconolactone (1 mmole).
  • In another process, DL-lactic acid 88% in water, 103 mg (90 mg lactic acid, 1 mmole) was added to the above stock solution 8 ml which contained 155 mg (0.5 mmole) fluoxetine base. The formation of a molecular complex between lactic acid and fluoxetine was complete as shown by the pH of the solution changing from 9.1 to 3.8. Propylene glycol (1 ml) was added and ethanol 1 ml was added to make the final volume to 10 ml. The topical composition thus prepared had pH 3.8 and contained 1.55% fluoxetine (0.5 mmole) in molecular complex with 0.9% DL-lactic acid (1 mmole).
  • EXAMPLE 13
  • Tadalafil hydrochloride known as Cialis is an oral treatment for erectile dysfunction. The following was a typical process to convert and incorporate an oral drug in tablet form into a composition comprising molecular complex for topical administration.
  • Tadalafil hydrochloride (Cialis) powder 213 mg (0.5 mmole) from oral tablets, each containing 20 mg tadalafil, was suspended in water (18 ml), and 1N sodium hydroxide 0.5 ml (0.5 mmole) was slowly added to generate tadalafil free base. Ethanol (18 ml) was added to dissolve tadalafil base and the mixture had pH 10.8. This mixture (36 ml) was used as a stock solution for the preparation of topical compositions comprising molecular complex as follows.
  • Gluconolactone 178 mg (1 mmole) was added to the above stock solution (18 ml) that contained 97 mg (0.25 mmole) tadalafil base. The formation of a molecular complex between gluconolactone and tadalafil was complete as shown by the pH of the solution changing from 10.8 to 4.7. Propylene glycol (2 ml) was added. The topical composition thus prepared had pH 4.7 and contained 0.485% tadalafil (0.25 mmole) in molecular complex with 0.89% gluconolactone (1 mmole).
  • In another process, glycolic acid 76 mg (1 mmole) was added to the above stock solution (18 ml) that contained 97 mg (0.25 mmole) tadalafil base. The formation of a molecular complex between glycolic acid and tadalafil was complete as shown by the pH of the solution changing from 10.8 to 3.7. Propylene glycol 2 ml was added. The topical composition thus prepared had pH 3.7 and contained 0.485% tadalafil (0.25 mmole) in molecular complex with 0.38% glycolic acid (1 mmole).
  • EXAMPLE 14
  • Vardenafil hydrochloride known as Levitra is an oral treatment for erectile dysfunction. The following was another example to convert and incorporate an oral drug in tablet form into a composition comprising molecular complex for topical administration.
  • Vardenafil hydrochloride (Levitra) powder 308 mg (0.5 mmole) from oral tablets, each containing 20 mg vardenafil, was suspended in water 10 ml, and 1N sodium hydroxide 0.5 ml (0.5 mmole) was slowly added to generate vardenafil free base. Ethanol 1 (0 ml) was added to dissolve vardenafil base, and the mixture had pH 8.9. This mixture (20 ml) was used as a stock solution for the preparation of topical compositions comprising molecular complex as follows.
  • DL-Lactic acid 88% in water, 103 mg (90 mg lactic acid, 1 mmole) was added to the above stock solution (10 ml) that contained 145 mg (0.25 mmole) vardenafil base. The formation of molecular complex between lactic acid and vardenafil was complete as shown by the pH of the solution changing from 8.9 to 3.9. The topical composition thus prepared had pH 3.9 and contained 1.45% (0.25 mmole) vardenafil in molecular complex with 0.9% DL-lactic acid (1 mmole).
  • In another process, DL-mandelic acid 152 mg (1 mmole) was added to the above stock solution (10 ml) that contained 145 mg (0.25 mmole) vardenafil base. The formation of molecular complex between mandelic acid and vardenafil was complete as shown by the pH of the solution changing from 8.9 to 4.0. The topical composition thus prepared had pH 4.0 and contained 1.45% (0.25 mmole) vardenafil in molecular complex with 1.52% DL-mandelic acid (1 mmole).
  • The invention has been described with reference to particularly preferred embodiments and examples. Those skilled in the art will appreciate that various modifications may be made to the invention without departing from the spirit and scope thereof.

Claims (52)

1. A composition comprising a molecular complex formed between:
an alkaline pharmaceutical drug; and
at least one agent selected from the group consisting of a hydroxyacid, a polyhydroxy acid, a related acid, a lactone form of these acids, and mixtures thereof,
wherein the alkaline pharmaceutical drug is selected from the group consisting of abacavir, adefovir dipivoxil, adenosine, alfuzosin, almotriptan, amlodipine, anagrelide, anastrozole, apomorphine, aprepitant, aripiprazole, atazanavir, atomoxetine, azathioprine, azelastine, azithromycin, benazepril, bendroflumethiazide, benzonatate, brimonidine, buprenorphine, butenafine, cabergoline, candesartan cilexetil, cefditoren pivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine, cevimeline, cilostazol, cinacalcet, ciprofloxacin, cladribine, clarithromycin, clomiphene, clopidogrel, cyclobenzaprine, cytarabine, dacarbazine, dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine, delavirdine, desloratadine, desmopressin, dexmethylphenidate, dexrazoxane, dextroamphetamine, didanosine, diltiazem, dipyridamole, dofetilide, dolasetron, donepezil, dorzolamide, doxorubicin, doxycycline, duloxetine, eflornithine, eletriptan, emtricitabine, enalapril, epirubicin, eptifibatide, escitalopram, esmolol, esomeprazole, estazolam, famciclovir, famotidine, felodipine, fexofenadine, flecainide, fluconazole, flucytosine, formoterol, galantamine, gatifloxacin, gefitinib, gemcitabine, gemifloxacin, haloperidol, homatropine, hydrochlorothiazide, hydromorphone, hyoscyamine, idarubicin, imatinib, indinavir, irinotecan, itraconazole, ketotifen, lamivudine, lansoprazole, letrozole, leuprolide, levalbuterol, levofloxacin, linezolid, loperamide, mebendazole, memantine, mercaptopurine, metformin, methylphenidate, midodrine, miglustat, mitoxantrone, moexiprilat, moxifloxacin, nalbuphine, nalmefene, nelfinavir, nevirapine, nicardipine, nimodipine, nisoldipine, nizatidine, octreotide, ofloxacin, olmesartan medoxomil, olopatadine, omeprazole, oxybutynin, oxycodone, palonosetron, pemoline, penciclovir, pentostatin, pentoxifylline, pergolide, pioglitazone, procarbazine, propafenone, propoxyphene, quinapril, quinupristin, ribavirin, rifampin, rifapentine, rifaximin, riluzole, rimantadine, rivastigmine, rizatriptan, sibutramine, sildenafil, streptomycin, sulfamethoxazole, sulfisoxazole, tadalafil, tegaserol, telithromycin, telmisartan, temozolomide, tenofovir disoproxil, terazosin, thiabendazole, thiothixene, tiagabine, tinidazole, tirofiban, tobramycin, tolterodine, tramadol, trimethoprim, trimipramine, tromethamine, vardenafil, voriconazole, zafirlukast, zaleplon, zolmitriptan, zolpidem, and mixtures thereof.
2. The composition as claimed in claim 1, wherein the hydroxyacid is an alkyl alpha hydroxyacid represented by the formula:

R1R2C(OH)COOH
wherein R1 and R2 may be independently H or alkyl group, and the alkyl alpha hydroxyacid may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical.
3. The composition as claimed in claim 2, wherein the alkyl group is selected from one or more of the group consisting of methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl, stearyl, and mixtures thereof.
4. The composition as claimed in claim 2, wherein the alkyl alpha hydroxyacid is selected from the group consisting of 2-hydroxyethanoic acid (glycolic acid), 2-hydroxypropanoic acid (lactic acid), 2-methyl-2-hydroxypropanoic acid (methyllactic acid), 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid, 2-hydroxyeicosanoic acid (alpha hydroxyarachidonic acid), 2-hydroxytetraeicosanoic acid (cerebronic acid), 2-hydroxytetraeicosenoic acid (alpha hydroxynervonic acid), and mixtures thereof.
5. The composition as claimed in claim 1, wherein the hydroxyacid is an aralkyl hydroxyacid represented by the following formula:

R1R2C(OH)COOH
wherein R1 and R2 may be independently H, aryl, or aralkyl group, and the aralkyl hydroxyacid may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical.
6. The composition as claimed in claim 5, wherein the aryl group is selected from the group consisting of phenyl, diphenyl, biphenyl, naphthyl, and mixtures thereof.
7. The composition as claimed in claim 5, wherein the aralkyl group is selected from the group consisting of phenylmethyl(benzyl), phenylethyl, phenylpropyl, diphenylmethyl, diphenylethyl, biphenylmethyl, naphthylmethyl group, and mixtures thereof.
8. The composition as claimed in claim 5, wherein the aralkyl hydroxyacid is selected from the group consisting of 2-phenyl-2-hydroxyethanoic acid (mandelic acid), 2,2-diphenyl-2-hydroxyethanoic acid (benzilic acid), 3-phenyl 2-hydroxypropanoic acid (3-phenyllactic acid), 2-phenyl-2-methyl-2-hydroxyethanoic acid (atrolactic acid, 2-phenyllactic acid), and mixtures thereof.
9. The composition as claimed in claim 1, wherein the hydroxyacid is a polycarboxyy alpha hydroxyacid represented by the following formula:

R1R2C(OH)COOH
where R1 and R2 may be independently H, COOH, CH2COOH or CHOHCOOH, and the polycarboxy AHAs may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical.
10. The composition as claimed in claim 9, wherein the polycarboxy alpha hydroxyacid is selected from the group consisting of 2-hydroxypropane-1,3-dioic acid (tartronic acid), 2-hydroxybutane-1,4-dioic acid (malic acid), 2,3-dihydroxybutane-1,4-dioic acid (tartaric acid), 2-hydroxy-2-carboxypentane-1,5-dioic acid (citric acid), isocitric acid, and mixtures thereof.
11. The composition as claimed in claim 1, wherein the hydroxyacid is a beta hydroxyacid represented by the following formula:

R1R2C(OH)CHR3COOH
where R1, R2, R3 may be H, alkyl, aryl or aralkyl group, and where the beta hydroxyacid may exist as stereoisomers as D, L and DL or R, S and RS forms when R1 and R2 are not identical or R3 is not H.
12. The composition as claimed in claim 11, wherein the beta hydroxyacid is selected from the group consisting of 3-hydroxypropanoic acid (β-hydroxypropanoic acid), 3-hydroxybutanoic acid (β-hydroxybutanoic acid), 3-hydroxypentanoic acid, 3-hydroxy-2-phenylpropanoic acid (tropic acid), and mixtures and combinations thereof.
13. The composition as claimed in claim 1, wherein the hydroxyacid is a polyhydroxy acid.
14. The composition as claimed in claim 13, wherein the polyhydroxy acid is selected from the group consisting of aldonic acids, aldaric acids, alduronic acids, and mixtures thereof.
15. The composition as claimed in claim 14, wherein the aldonic acid is represented by the following formula.

R(CHOH)nCHOHCOOH
where R is H or alkyl group, and n is an integer from 1-6, and where the aldonic acids may exist as stereoisomers as D, L and DL, or R, S and RS forms.
16. The composition as claimed in claim 15, wherein the aldonic acid is selected from the group consisting of 2,3-dihydroxypropanoic acid (glyceric acid), 2,3,4-trihydroxybutanoic acids (stereoisomers; erythronic acid and erythronolactone, threonic acid and threonolactone), 2,3,4,5-tetrahydroxypentanoic acids (stereoisomers; ribonic acid and ribonolactone, arabinoic acid and arabinolactone, xylonic acid and xylonolactone, lyxonic acid and lyxonolactone), 2,3,4,5,6-pentahydroxyhexanoic acids (stereoisomers; allonic acid and allonolactone, altronic acid and altronolactone, gluconic acid and gluconolactone, mannoic acid and mannolactone, gulonic acid and gulonolactone, idonic acid and idonolactone, galactonic acid and galactonolactone, talonic acid and talonolactone), 2,3,4,5,6,7-hexahydroxyheptanoic acids (stereoisomers; alloheptonic acid and alloheptonolactone, altroheptonic acid and altroheptonolactone, glucoheptonic acid and glucoheptonolactone, mannoheptonic acid and mannoheptonolactone, guloheptonic acid and guloheptonolactone, idoheptonic acid and idoheptonolactone, galactoheptonic acid and galactoheptonolactone, taloheptonic acid and taloheptonolactone), and mixtures thereof.
17. The composition as claimed in claim 14, wherein the aldaric acid is represented by the following formula:

HOOC(CHOH)nCHOHCOOH
where n is an integer from 1-4, and where the aldaric acids may exist as stereoisomers as D, L and DL, or R, S and RS forms.
18. The composition as claimed in claim 17, wherein the aldaric acids is selected from the group consisting of 2,3-dihydroxybutane-1,4-dioic acids (stereoisomers; erythraric acid and threaric acid, also known as tartaric acid), 2,3,4-trihydroxypentane-1,5-dioic acids (stereoisomers; ribaric acid and ribarolactone, arabaric acid and arabarolactone, xylaric acid and xylarolactone, lyxaric acid and lyxarolactone), 2,3,4,5-tetrahydroxyhexane-1,6-dioic acids (stereoisomers; allaric acid and allarolactone, altraric acid and altrarolactone, glucaric acid and glucarolactone, mannaric acid and mannarolactone, gularic acid and gularolactone, idaric acid and idarolactone, galactaric acid and galactarolactone, talaric acid and talarolactone), 2,3,4,5,6-pentahydroxyheptane-1,7-dioic acids (stereoisomers; alloheptaric acid and alloheptarolactone, altroheptaric acid and altroheptarolactone, glucoheptaric acid and glucoheptarolactone, mannoheptaric acid and mannoheptarolactone, guloheptaric acid and guloheptarolactone, idoheptaric acid and idoheptarolactone, galactoheptaric acid and galactoheptarolactone, taloheptaric acid and taloheptarolactone), and mixtures thereof.
19. The composition as claimed in claim 14, wherein the alduronic acid is represented by the following formula:

HOOC(CHOH)nCHOHCHO
where n is an integer from 1-4, and where the alduronic acids may exist as stereoisomers as D, L and DL, or R, S and RS forms.
20. The composition as claimed in claim 19, wherein the alduronic acid is selected from the group consisting of erythruronic acid, threuronic acid, riburonic acid and riburonolactone, araburonic acid and araburonolactone, xyluronic acid and xyluronolactone, lyxuronic acid and lyxuronolactone, alluronic acid and alluronolactone, altruronic acid and altruronolactone, glucuronic acid and glucuronolactone, mannuronic acid and mannuronolactone, guluronic acid and guluronolactone, iduronic acid and iduronolactone, galacturonic acid and galacturonolactone, taluronic acid and taluronolactone, allohepturonic acid and allohepturonolactone, altrohepturonic acid and altrohepturonolactone, glucohepturonic acid and glucohepturonolactone, mannohepturonic acid and mannohepturonolactone, gulohepturonic acid and gulohepturonolactone, idohepturonic acid and idohepturonolactone, galactohepturonic acid and galactohepturonolactone, talohepturonic acid and talohepturonolactone, and mixtures thereof.
21. The composition as claimed in claim 1, wherein the hydroxyacid is an aldobionic acid represented by the following generic formula:

H(CHOH)m (CHOR) (CHOH)n COOH
where m and n are integers independently from 0-7, and R is a monosaccharide, and wherein the aldobionic acid exists as stereoisomers as D, L and DL, or R, S and RS forms, and can form intramolecular lactones by the removal of one mole of water between the carboxyl group and one hydroxyl group.
22. The composition as claimed in claim 1, wherein the hydroxyacid is an aldobionic acid selected from the group consisting of lactobionic acid and lactobionolactone, isolactobionic acid and isolactobionolactone, maltobionic acid and maltobionolactone, isomaltobionic acid and isomaltobionolactone, cellobionic acid and cellobionolactone, gentiobionic acid and gentiobionolactone, kojibionic acid and kojibionolactone, laminaribionic acid and laminaribionolactone, melibionic acid and melibionolactone, nigerobionic acid and nigerobionolactone, rutinobionic acid and rutinobionolactone, sophorobionic acid and sophorobionolactone, and mixtures thereof.
23. The composition as claimed in claim 1, wherein the related acids are selected from the group consisting of alpha ketoacids, miscellaneous hydroxyacids, oligomers of hydroxyacids, and mixtures thereof.
24. The composition as claimed in claim 23, wherein the alpha ketoacid is represented by the following formula:

(Ra)COCOOH
wherein Ra is H, alkyl, aralkyl or aryl group of saturated or unsaturated, isomeric or non-isomeric, straight or branched chain or cyclic form, having 1 to 25 carbon atoms, and in addition Ra may carry F, Cl, Br, I, OH, CHO, COOH and alkoxyl group having 1 to 9 carbon atoms.
25. The composition as claimed in claim 24, wherein the alpha ketoacid is selected from the group consisting of: 2-ketoethanoic acid (glyoxylic acid), 2-ketopropanoic acid (pyruvic acid), 2-phenyl-2-ketoethanoic acid (benzoylformic acid), 3-phenyl-2-ketopropanoic acid (phenylpyruvic acid), 2-ketobutanoic acid, 2-ketopentanoic acid, 2-ketohexanoic acid, 2-ketoheptanoic acid, 2-ketooctanoic acid, 2-ketododecanoic acid, and mixtures thereof.
26. The composition as claimed in claim 23, wherein the miscellaneous hydroxyacid is selected from the group consisting of: agaricic acid, aleuritic acid, citramalic acid, glucosaminic acid, galactosaminic acid, 2-keto-gulonic acid and 2-keto-gulonolactone, mannosaminic acid, mevalonic acid and mevalonolactone, pantoic acid and pantolactone, quinic acid (1,3,4,5-tetrahydroxycyclohexanecarboxylic acid), piscidic acid (4-hydroxybenzyltartaric acid), ascorbic acid (3-oxo-L-gulofuranolactone), Isoascorbic acid (D-erythro-hex-2-enonic acidr-lactone), 2-hexulosonic acids (isomers; arabino-2-hexulosonicacid, xylo-2-hexulosonic acid, ribo-2-hexulosonic acid, lyxo-2-hexulosonic acid), 5-hexulosonic acids (isomers; arabino-5-hexulosonic acid, xylo-5-hexulosonic acid, ribo-5-hexulosonic acid, lyxo-5-hexulosonic acid), and mixtures thereof.
27. The composition as claimed in claim 23, wherein the oligomer of hydroxyacid is represented by the following general formula:

(AHA)m - - - n(H2O)
wherein, AHA is a hydroxyacid, m=2-10, with a preferred number of 2-4, and n=m−1, and wherein the AHA in each monomer needs not be identical.
28. The composition as claimed in claim 27, wherein the oligomer of hydroxyacid is selected from the group consisting of glycolyl glycolate, lactyl lactate, citryl citrate, glycoly citrate, citryl glycolate, lactyl citrate, citryl lactate, malyl malate, malyl glycolate, tartaryl tartrate, tartaryl glycolate, glycolyl tartrate, glycolyl glycoly glycolate, lactyl lactyl lactate, and mixtures thereof.
29. The composition as claimed in claim 1, wherein the hydroxacid, polyhydroxy acid, related acid, or lactone of these acids is selected from one or more of the group consisting of glycolic acid, lactic acid, gluconic acid, gluconolactone, ribonic acid, ribonolactone, galactonic acid, galactonolactone, glucoheptonic acid, glucoheptonolactone, glucuronic acid, glucuronolactone, galacturonic acid, galacturonolactone, glucaric acid, glucarolactone, galactaric acid, galactarolactone, lactobionic acid, maltobionic acid, and mixtures thereof.
30. The composition as claimed in claim 1, wherein the molar ratio of the alkaline pharmaceutical drug to the hydroxyacid or polyhydroxy acid or related acid or lactone is within the range of from about 1:0.1 to about 1:40.
31. The composition as claimed in claim 1, wherein molecular weight of the hydroxyacid, or polyhydroxyacid, or related acid, or lactone form thereof is within the range of from about 50 to about 1000.
32. The composition as claimed in claim 1, further comprising pharmaceutical and other topical agents selected from the group consisting of: those that improve or eradicate age spots, keratoses and wrinkles; local analgesics and anesthetics; antiacne agents; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antidandruff agents; antidermatitis agents; antihistamine agents; antipruritic agents; antiemetics; antimotionsickness agents; antiinflammatory agents; antihyperkeratolytic agents; antiperspirants; antipsoriatic agents; antiseborrheic agents; hair conditioners and hair treatment agents; antiaging and antiwrinkle agents; sunblock and sunscreen agents; skin lightening agents; depigmenting agents; vitamins; corticosteroids; tanning agents; humectants; hormones; retinoids; gum disease or oral care agents; topical cardiovascular agents; corn, callus and wart removing agents; dipilating agents, and mixtures and combinations thereof.
33. The composition as claimed in claim 1, further comprising one or more additional agents selected from the group consisting of aclovate, acetylsalicylic acid, adapalene, aluminum acetate, aluminum chloride, aluminum hydroxide, aluminum chlorohydroxide, aminobenzoic acid (PABA), aminocaproic acid, aminosalicylic acid, anthralin, ascorbic acid, ascoryl palimate, azelaic acid, bacitracin, beclomethasone dipropionate, benzophenone, benzoyl peroxide, betamethasone dipropionate, betamethasone valerate, calcipotriene, camphor, capsaicin, carbamide peroxide, chitosan, chloroxylenol, ciclopirox, clobetasol propionate, coal tar, dehydroepiandrosterone, desoximetasone, dexamethasone, estradiol, ethinyl estradiol, fluocinonide, fluocinolone acetonide, 5-fluorouracil, griseofulvin, hexylresorcinol, homosalate, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrogen peroxide, hydroquinone, hydroquinone monoether, hydroxyzine, ibuprofen, indomethacin, kojic acid, menthol, methyl nicotinate, methyl salicylate, monobenzone, naproxen, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate 0, permethrin, phenol, piperonyl butoxide, povidone iodine, resorcinol, retinal, 13-cis retinoic acid, retinoic acid, retinol, retinyl acetate, retinyl palmitate, salicylamide, salicylic acid, selenium sulfide, shale tar, sulfur, triamcinolone diacetate, triamcinolone acetonide, triamcinolone hexacetonide, triclosan, undecylenic acid, urea, vitamin E acetate, wood tar, zinc pyrithione, N-acetyl-prolinamide, N-acetyl-lysine, N-acetyl-ornithine, N-acetyl-glucosamine, and mixtures thereof.
34. A method of forming a molecular complex between an alkaline pharmaceutical drug as claimed in claim 1, and at least one of a hydroxyacid, polyhydroxyacid, related acid, and lactone, comprising:
dissolving the alkaline pharmaceutical drug and an alkali in a suitable reaction medium to form a free base of the pharmaceutical drug;
optionally separating the free base of the pharmaceutical drug from the reaction medium; and
adding at least one of a hydroxyacid, a polyhydroxyacid, a related acid, or lactones thereof to the free base in a suitable reaction medium to form a molecular complex.
35. The method as claimed in claim 34, wherein the free base of the pharmaceutical drug is separated from the reaction medium.
36. The method as claimed in claim 34, wherein the reaction medium used to form the free base of the pharmaceutical drug is water.
37. The method as claimed in claim 34, wherein the alkali added to the alkaline pharmaceutical drug is an inorganic alkali.
38. The method as claimed in claim 34, wherein the free base of the alkaline pharmaceutical drug is formed as a precipitate or oily product that then is separated from the reaction medium.
39. The method as claimed in claim 34, wherein the reaction medium used to form the molecular complex is water, and wherein the free base of the alkaline pharmaceutical drug is suspended in the water.
40. The method as claimed in claim 39, wherein the reaction medium additionally comprises a solvent selected from the group consisting of ethanol, propylene glycol, butylene glycol, and mixtures thereof.
41. The method as claimed in claim 34, wherein the molecular complex is formed when the pH of the reaction medium has changed.
42. The method as claimed in claim 34, wherein the amount of hydroxyacid, polyhydroxy acid, related acid, or lactone form thereof is within the range of from about 0.1 to about 40 moles per mole of pharmaceutical drug.
43. The method as claimed in claim 42, wherein the amount of hydroxyacid, polyhydroxy acid, related acid, or lactone form thereof is within the range of from about 0.5 to about 5 moles per mole of pharmaceutical drug.
44. A method of treating a cosmetic condition or dermatologic indication in a subject comprising topically administering a therapeutically effective amount of the composition as claimed in claim 1 to a subject in need thereof.
45. The method as claimed in claim 44, wherein the pH of the composition is within the range of from about 2.0 to about 7.0
46. The method as claimed in claim 45, wherein the pH of the composition is within the range of from about 3.0 to about 5.0.
47. The method as claimed in claim 44, wherein the composition is in a form selected from the group consisting of lotion, cream, ointment, and gel.
48. The method as claimed in claim 47, wherein the composition additionally includes a cosmetically or dermatologically acceptable excipient.
49. The method as claimed in claim 44, wherein the method treats, heals or prevents a cosmetic condition or dermatological indication.
50. The method as claimed in claim 49, wherein the method treats, heals, or prevents a cosmetic condition or dermatological indication selected from the group consisting cosmetic and clinical signs of changes associated with intrinsic or extrinsic aging; the damages caused by extrinsic factors such as sunlight, air pollution, wind, cold, dampness, heat, chemicals, smoke, cigarette smoking, and radiations including electromagnetic radiations and ionizing radiations; mucosa; skin erythema; inflammation or reaction caused by internal or external factors; and mixtures thereof.
51. The method as claimed in claim 49, wherein the cosmetic condition or dermatological indication is selected from the group consisting of: disturbed keratinization; inflammation; defective syntheses of dermal components; changes associated with intrinsic and extrinsic aging of skin, nail and hair; dryness or looseness of skin, nail and hair; xerosis; ichthyosis; palmar and plantar hyperkeratoses; uneven and rough surface of skin, nail and hair; dandruff; Darier's disease; lichen simplex chronicus; keratoses; acne; pseudofolliculitis barbae; dermatoses; eczema; psoriasis; pruritus; warts; herpes; age spots; lentigines; melasmas; blemished skin; hyperkeratoses; hyperpigmented or hypopigmented skin; abnormal or diminished syntheses of collagen, glycosaminoglycans, proteoglycans and elastin as well as diminished levels of such components in the dermis; stretch marks; skin lines; fine lines; wrinkles; thinning of skin, nail plate and hair; skin thickening due to elastosis of photoaging, loss or reduction of skin, nail and hair resiliency, elasticity and recoilability; lack of skin, nail and hair lubticants and luster; dull and older-looking skin, nail and hair; fragility and splitting of nail and hair, or used as to lighten the skin.
52. The method as claimed in claim 51, wherein the skin changes associated with aging are selected from the group consisting of progressive thinning of skin, fragile skin, deepening of skin lines and fine lines, wrinkles including fine and coarse wrinkles, lusterless skin surface, coarse and uneven skin, loss of skin elasticity and recoilability, blemished and leathery skin, loss of skin lubricating substances, increased numbers of blotches and mottles, nodules, pre-cancerous lesions, pigmented spots and mottled skin, changes in qualities and quantities of collagen and elastic fibers, solar elastosis, decrease in collagen fibers, diminution in the number and diameter of elastic fibers in the papillary dermis, atrophy of the dermis, stretch marks, reduction in subcutaneous adipose tissue and deposition of abnormal elastic materials in the upper dermis, yellowing skin, telangiectatic skin, and older-looking skin.
US11/050,434 2004-03-04 2005-02-04 Bioavailability and improved delivery of alkaline pharmaceutical drugs Abandoned US20050196418A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/050,434 US20050196418A1 (en) 2004-03-04 2005-02-04 Bioavailability and improved delivery of alkaline pharmaceutical drugs
PCT/US2006/003917 WO2006084174A2 (en) 2005-02-04 2006-02-06 Improved bioavailability and improved delivery of alkaline pharmaceutical drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/792,273 US20040214215A1 (en) 2003-03-07 2004-03-04 Bioavailability and improved delivery of alkaline pharmaceutical drugs
US11/050,434 US20050196418A1 (en) 2004-03-04 2005-02-04 Bioavailability and improved delivery of alkaline pharmaceutical drugs

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/792,273 Continuation-In-Part US20040214215A1 (en) 2003-03-07 2004-03-04 Bioavailability and improved delivery of alkaline pharmaceutical drugs

Publications (1)

Publication Number Publication Date
US20050196418A1 true US20050196418A1 (en) 2005-09-08

Family

ID=36777983

Family Applications (1)

Application Number Title Priority Date Filing Date
US11/050,434 Abandoned US20050196418A1 (en) 2004-03-04 2005-02-04 Bioavailability and improved delivery of alkaline pharmaceutical drugs

Country Status (2)

Country Link
US (1) US20050196418A1 (en)
WO (1) WO2006084174A2 (en)

Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040180854A1 (en) * 2001-11-13 2004-09-16 Yu Ruey J. Oligosaccharide aldonic acids and their topical use
US20060008520A1 (en) * 2004-04-01 2006-01-12 Lerner E I Delayed release formulations of 6-mercaptopurine
US20060009473A1 (en) * 2004-04-01 2006-01-12 Lerner E I Formulations of 6-mercaptopurine
US20070183995A1 (en) * 2006-02-09 2007-08-09 Conopco, Inc., D/B/A Unilever Compounds useful as agonists of A2A adenosine receptors, cosmetic compositions with A2A agonists and a method for using the same
WO2007147052A2 (en) * 2006-06-14 2007-12-21 Dr. Reddy's Laboratories Limited Topical compositions
WO2008001200A2 (en) * 2006-06-29 2008-01-03 Antares Pharma Ipl Ag Transdermal composition having enhanced color stability
EP1875914A1 (en) * 2006-07-07 2008-01-09 Teva Pharmaceutical Industries Ltd. Solid compositions comprising tadalafil and at least one carrier
CN100369889C (en) * 2006-09-15 2008-02-20 中国科学院山西煤炭化学研究所 Process for synthesizing salicylamide
US20080059313A1 (en) * 2006-08-30 2008-03-06 Oblong John E Hair care compositions, methods, and articles of commerce that can increase the appearance of thicker and fuller hair
US20090098211A1 (en) * 2007-04-25 2009-04-16 Ilan Zalit Solid dosage forms
US20090263482A1 (en) * 2008-04-18 2009-10-22 Vered Rosenberger Treatment of inflammatory bowel disease with 6-mercaptopurine
WO2009127825A1 (en) * 2008-04-16 2009-10-22 Cipla Limited Topical combinations comprising an antimycotic agent and an antiviral agent
US20100179159A1 (en) * 2007-06-22 2010-07-15 Ratiopharm Gmbh Method for the production of a medicament containing tadalafil
US20100197792A1 (en) * 2008-12-19 2010-08-05 Merz Pharma Gmbh & Co. Kgaa 1-Amino-Alkylcyclohexane derivatives for the treatment of inflammatory skin diseases
US20110171149A1 (en) * 2010-01-06 2011-07-14 Yoko Niki Skin Lightening Compositions
US8053427B1 (en) 2010-10-21 2011-11-08 Galderma R&D SNC Brimonidine gel composition
US20130004577A1 (en) * 2006-06-13 2013-01-03 Nippon Shinyaku Coated tablet
US8399519B2 (en) 2008-12-19 2013-03-19 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases
US8513247B2 (en) 2010-03-26 2013-08-20 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US8586586B2 (en) 2003-05-27 2013-11-19 Galderma Laboratories Inc. Methods and compositions for treating or preventing erythema
WO2013187891A1 (en) * 2012-06-13 2013-12-19 Alain Martin Method for treating a pulmonary disease state in mammals by up regulating indigenous in vivo levels of inflammatory agents in mammalian cells
ITBO20120368A1 (en) * 2012-07-06 2014-01-07 Alfa Wassermann Spa COMPOSITIONS INCLUDING RIFAXIMINA AND AMINO ACIDS, RIFAXIMINE CRYSTALS DERIVING FROM SUCH COMPOSITIONS AND THEIR USE.
WO2014105480A1 (en) * 2012-12-28 2014-07-03 Teikoku Pharma Usa, Inc. Extended buprenorphine transdermal delivery compositions and methods for using the same
US8835382B2 (en) 2009-11-23 2014-09-16 Cubist Pharmaceuticals, Inc. Lipopeptide compositions and related methods
WO2014152382A1 (en) * 2013-03-15 2014-09-25 Strategic Science & Technologies, Llc Transdermal delivery of sildenafil and other phosphodiesterase type 5 inhibitors
CN104095766A (en) * 2014-07-14 2014-10-15 拉芳家化股份有限公司 Sophorolipid-enhanced anti-dandruff composition and application thereof
WO2014172344A1 (en) * 2013-04-16 2014-10-23 Alpha To Omega Pharmaceutical Consultants, Inc. Pharmaceutical compositions
US20140350049A1 (en) * 2011-11-29 2014-11-27 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for the treatment of darier disease
US8916562B2 (en) 2010-03-26 2014-12-23 Galderma Research & Development Snc Methods and compositions for safe and effective treatment of telangiectasia
US8992897B2 (en) 2010-01-06 2015-03-31 Elc Management Llc Skin lightening compositions
US9050365B2 (en) 2004-04-19 2015-06-09 Strategic Science & Technologies, Llc Transdermal delivery of beneficial substances effected by a hostile biophysical environment
US9072659B2 (en) 2009-06-24 2015-07-07 Strategic Science & Technologies, Llc Topical composition containing naproxen
CN104784185A (en) * 2015-04-03 2015-07-22 北京太禾利和医药科技有限公司 Nevirapine drug composition and preparation method thereof
US9155701B2 (en) 2009-06-24 2015-10-13 Strategic Science & Technologies, Llc Delivery of ibuprofen and other compounds
US9226909B2 (en) 2004-04-19 2016-01-05 Strategic Science & Technologies, Llc Beneficial effects of increasing local blood flow
US9289495B2 (en) 2010-12-29 2016-03-22 Strategic Science & Technologies, Llc Systems and methods for treatment of allergies and other indications
AU2013267022B2 (en) * 2010-01-06 2016-04-21 Elc Management Llc Skin lightening compositions
AU2015200590B2 (en) * 2010-01-06 2016-05-05 Elc Management Llc Skin lightening compositions
US9463158B2 (en) 2009-06-24 2016-10-11 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9498442B2 (en) 2010-03-05 2016-11-22 Alfa Wassermann S.P.A. Rifaximin powder, process for preparing the same an controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect
US20170000819A1 (en) * 2015-07-02 2017-01-05 Veloce Biopharma, Llc Novel ophthalmic composition and methods of use
WO2017007910A1 (en) 2015-07-09 2017-01-12 Galderma S.A. Method of reducing hair loss associated with chemotherapy
WO2017161136A1 (en) * 2016-03-18 2017-09-21 Oak Crest Institute Of Science Acid salts for vaginal drug delivery
CN107349207A (en) * 2016-05-10 2017-11-17 刘民祥 It is a kind of except the medicine of acne
US20180200289A1 (en) * 2015-07-02 2018-07-19 Veloce Biopharma, Llc Novel ophthalmic composition and methods of use
US10123966B2 (en) 2013-05-16 2018-11-13 The Procter And Gamble Company Hair thickening compositions and methods of use
US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use
US10258610B2 (en) 2011-07-29 2019-04-16 Alfasigma S.P.A. Pharmaceutical compositions comprising rifaximin, processes for their preparation and their use in the treatment of vaginal infections
US10285944B2 (en) 2005-03-07 2019-05-14 Alfasigma S.P.A. Gastroresistant pharmaceutical formulations containing rifaximin
JP2019081747A (en) * 2017-10-30 2019-05-30 株式会社 資生堂 Hair treatment agent
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
JP2019535795A (en) * 2016-11-28 2019-12-12 セリックス バイオ プライヴェート リミテッドCellix Bio Private Limited Compositions and methods for the treatment of oral infections
CN110604730A (en) * 2018-06-15 2019-12-24 镇学初 Application of metformin salt in treatment of cerebral infarction
US10703763B2 (en) 2005-03-03 2020-07-07 Alfasigma S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US10828308B2 (en) 2015-10-16 2020-11-10 Hadasit Medical Research Services And Development Ltd. Treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis with delayed-release 6-mercaptopurine
US11485730B2 (en) 2016-11-28 2022-11-01 Cellix Bio Private Limited Compositions and methods for the treatment of fungal infections
US11684624B2 (en) 2009-06-24 2023-06-27 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009018133A1 (en) * 2009-04-15 2010-11-11 Agon Pharma Gmbh Pharmaceutical composition for the treatment of dermatological autoimmune diseases
WO2011036676A2 (en) * 2009-09-23 2011-03-31 Ashwini Nangia Stable cocrystals of temozolomide
PL390079A1 (en) * 2009-12-30 2011-07-04 Zakłady Farmaceutyczne POLPHARMA Spółka Akcyjna Process for the preparation of vardenafil and its isolation as a salt with citric acid and a crystalline form of this salt
GR1008554B (en) 2014-06-12 2015-09-03 ΦΑΡΜΑΤΕΝ ΑΝΩΝΥΜΟΣ ΒΙΟΜΗΧΑΝΙΚΗ ΚΑΙ ΕΜΠΟΡΙΚΗ ΕΤΑΙΡΕΙΑ ΦΑΡΜΑΚΕΥΤΙΚΩΝ ΙΑΤΡΙΚΩΝ ΚΑΙ ΚΑΛΛΥΝΤΙΚΩΝ ΠΡΟΪΟΝΤΩΝ με δ.τ. ΦΑΡΜΑΤΕΝ, Pharmaceutical preparation containing an antifugal trizol factor - preparation method of the same
CN107249360B (en) * 2015-01-28 2020-04-28 惠州市吉瑞科技有限公司 Electronic cigarette and method for displaying residual amount of tobacco tar
MX2018004788A (en) * 2018-04-18 2019-10-21 Alparis Sa De Cv New rifaximin solid phases.
EP3860592A4 (en) * 2018-11-26 2023-04-19 Cellix Bio Private Limited Ophthalmic compositions and methods for the treatment of skin diseases and eye diseases

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4627429A (en) * 1986-02-28 1986-12-09 American Home Products Corporation Storage-stable transdermal adhesive patch
US4784857A (en) * 1986-06-03 1988-11-15 Smith And Nephew Associated Companies Plc Drug delivery device, its preparation and use
US5662925A (en) * 1994-12-21 1997-09-02 Theratech, Inc. Transdermal delivery system with adhesive overlay and peel seal disc
US5788983A (en) * 1989-04-03 1998-08-04 Rutgers, The State University Of New Jersey Transdermal controlled delivery of pharmaceuticals at variable dosage rates and processes
US5877212A (en) * 1997-04-16 1999-03-02 Yu; Ruey J. Molecular complex and control-release of alpha hydroxyacids
US6113940A (en) * 1997-03-03 2000-09-05 Brooke; Lawrence L. Cannabinoid patch and method for cannabis transdermal delivery
US6159485A (en) * 1999-01-08 2000-12-12 Yugenic Limited Partnership N-acetyl aldosamines, n-acetylamino acids and related n-acetyl compounds and their topical use
US6335023B1 (en) * 1999-06-30 2002-01-01 Ruey J. Yu Oligosaccharide aldonic acids and their topical use
US6620429B1 (en) * 1998-03-30 2003-09-16 Lts Lohmann Therapie-Systeme Ag Use of basic alkali metal salts for manufacturing transdermal therapeutic system

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2728167A1 (en) * 1994-12-15 1996-06-21 Cird Galderma COSMETIC OR DERMATOLOGICAL COMPOSITION IN THE FORM OF WATER EMULSION IN OIL WITH HIGH HYDROXYACID CONTENT
US6800668B1 (en) * 2001-01-19 2004-10-05 Intellipharmaceutics Corp. Syntactic deformable foam compositions and methods for making

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4627429A (en) * 1986-02-28 1986-12-09 American Home Products Corporation Storage-stable transdermal adhesive patch
US4784857A (en) * 1986-06-03 1988-11-15 Smith And Nephew Associated Companies Plc Drug delivery device, its preparation and use
US5788983A (en) * 1989-04-03 1998-08-04 Rutgers, The State University Of New Jersey Transdermal controlled delivery of pharmaceuticals at variable dosage rates and processes
US5662925A (en) * 1994-12-21 1997-09-02 Theratech, Inc. Transdermal delivery system with adhesive overlay and peel seal disc
US6113940A (en) * 1997-03-03 2000-09-05 Brooke; Lawrence L. Cannabinoid patch and method for cannabis transdermal delivery
US5877212A (en) * 1997-04-16 1999-03-02 Yu; Ruey J. Molecular complex and control-release of alpha hydroxyacids
US6620429B1 (en) * 1998-03-30 2003-09-16 Lts Lohmann Therapie-Systeme Ag Use of basic alkali metal salts for manufacturing transdermal therapeutic system
US6159485A (en) * 1999-01-08 2000-12-12 Yugenic Limited Partnership N-acetyl aldosamines, n-acetylamino acids and related n-acetyl compounds and their topical use
US6335023B1 (en) * 1999-06-30 2002-01-01 Ruey J. Yu Oligosaccharide aldonic acids and their topical use

Cited By (116)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100099632A1 (en) * 1999-06-30 2010-04-22 Yu Ruey J Oligosaccharide Aldonic Acids and Their Topical Use
US20110091403A1 (en) * 1999-06-30 2011-04-21 Yu Ruey J Oligosaccharide aldonic acids and their topical use
US7452545B2 (en) * 2001-11-13 2008-11-18 Yu Ruey J Oligosaccharide aldonic acids and their topical use
US20040180854A1 (en) * 2001-11-13 2004-09-16 Yu Ruey J. Oligosaccharide aldonic acids and their topical use
US8586586B2 (en) 2003-05-27 2013-11-19 Galderma Laboratories Inc. Methods and compositions for treating or preventing erythema
US10525009B2 (en) 2004-04-01 2020-01-07 Hadasit Medical Research Services And Development Ltd. Formulations of 6-mercaptopurine
US9375403B2 (en) 2004-04-01 2016-06-28 Teva Pharmaceutical Industries Ltd. Formulations of 6-mercaptopurine
US8653060B2 (en) 2004-04-01 2014-02-18 Teva Pharmaceutical Industries Ltd. Formulations of 6-mercaptopurine
US20090042914A1 (en) * 2004-04-01 2009-02-12 Teva Pharmaceuticals Usa, Inc. Delayed release formulations of 6-mercaptopurine
US8188067B2 (en) 2004-04-01 2012-05-29 Teva Pharmaceutical Industries Ltd. Formulations of 6-mercaptopurine
US9180097B2 (en) 2004-04-01 2015-11-10 Teva Pharmaceutical Industries Ltd. Formulations of 6-mercaptopurine
US20060009473A1 (en) * 2004-04-01 2006-01-12 Lerner E I Formulations of 6-mercaptopurine
US20060008520A1 (en) * 2004-04-01 2006-01-12 Lerner E I Delayed release formulations of 6-mercaptopurine
US9226909B2 (en) 2004-04-19 2016-01-05 Strategic Science & Technologies, Llc Beneficial effects of increasing local blood flow
US9050365B2 (en) 2004-04-19 2015-06-09 Strategic Science & Technologies, Llc Transdermal delivery of beneficial substances effected by a hostile biophysical environment
US10703763B2 (en) 2005-03-03 2020-07-07 Alfasigma S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US10285944B2 (en) 2005-03-07 2019-05-14 Alfasigma S.P.A. Gastroresistant pharmaceutical formulations containing rifaximin
US20070183995A1 (en) * 2006-02-09 2007-08-09 Conopco, Inc., D/B/A Unilever Compounds useful as agonists of A2A adenosine receptors, cosmetic compositions with A2A agonists and a method for using the same
US8617603B2 (en) * 2006-06-13 2013-12-31 Nippon Shinyaku Co., Ltd. Coated tablet
US20130004577A1 (en) * 2006-06-13 2013-01-03 Nippon Shinyaku Coated tablet
WO2007147052A2 (en) * 2006-06-14 2007-12-21 Dr. Reddy's Laboratories Limited Topical compositions
US20090247529A1 (en) * 2006-06-14 2009-10-01 Dr. Reddy's Laboratories Ltd. Topical compositions
US8431140B2 (en) * 2006-06-14 2013-04-30 Dr. Reddy's Laboratories, Inc. Topical compositions
EP2457560A1 (en) * 2006-06-14 2012-05-30 Dr Reddy's Laboratories Limited Topical compositions
WO2007147052A3 (en) * 2006-06-14 2008-09-18 Reddys Lab Ltd Dr Topical compositions
WO2008001200A3 (en) * 2006-06-29 2008-06-05 Antares Pharma Ipl Ag Transdermal composition having enhanced color stability
US20080233179A1 (en) * 2006-06-29 2008-09-25 Arnaud Grenier Transdermal composition having enhanced color stability
WO2008001200A2 (en) * 2006-06-29 2008-01-03 Antares Pharma Ipl Ag Transdermal composition having enhanced color stability
US20080009502A1 (en) * 2006-07-07 2008-01-10 Access Business Group International Llc Tadalafil solid composites
CN101500572B (en) * 2006-07-07 2013-08-21 特瓦制药工业有限公司 Solid compositions comprising tadalafil and at least one carrier
CN101500572A (en) * 2006-07-07 2009-08-05 特瓦制药工业有限公司 Solid compositions comprising tadalafil and at least one carrier
WO2008005039A1 (en) * 2006-07-07 2008-01-10 Teva Pharmaceutical Industries Ltd. Solid compositions comprising tadalafil and at least one carrier
KR101140110B1 (en) 2006-07-07 2012-06-04 테바 파마슈티컬 인더스트리즈 리미티드 Solid compositions comprising tadalafil and at least one carrier
EP1875914A1 (en) * 2006-07-07 2008-01-09 Teva Pharmaceutical Industries Ltd. Solid compositions comprising tadalafil and at least one carrier
US20080059313A1 (en) * 2006-08-30 2008-03-06 Oblong John E Hair care compositions, methods, and articles of commerce that can increase the appearance of thicker and fuller hair
CN100369889C (en) * 2006-09-15 2008-02-20 中国科学院山西煤炭化学研究所 Process for synthesizing salicylamide
US20090098211A1 (en) * 2007-04-25 2009-04-16 Ilan Zalit Solid dosage forms
US20100179159A1 (en) * 2007-06-22 2010-07-15 Ratiopharm Gmbh Method for the production of a medicament containing tadalafil
US9238007B2 (en) 2007-06-22 2016-01-19 Ratiopharm Gmbh Method for the production of a medicament containing tadalafil
WO2009127825A1 (en) * 2008-04-16 2009-10-22 Cipla Limited Topical combinations comprising an antimycotic agent and an antiviral agent
US20110104262A1 (en) * 2008-04-16 2011-05-05 Cipla Limited Topical Combinations Comprising an Antimycotic Agent and an Antiviral Agent
US20090263482A1 (en) * 2008-04-18 2009-10-22 Vered Rosenberger Treatment of inflammatory bowel disease with 6-mercaptopurine
US8680149B2 (en) 2008-12-19 2014-03-25 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases
US8399519B2 (en) 2008-12-19 2013-03-19 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of mast cell mediated diseases
US20100197792A1 (en) * 2008-12-19 2010-08-05 Merz Pharma Gmbh & Co. Kgaa 1-Amino-Alkylcyclohexane derivatives for the treatment of inflammatory skin diseases
US8394857B2 (en) 2008-12-19 2013-03-12 Merz Pharma Gmbh & Co. Kgaa 1-amino-alkylcyclohexane derivatives for the treatment of inflammatory skin diseases
US9457092B2 (en) 2009-06-24 2016-10-04 Strategic Science & Technologies, Llc Delivery of ibuprofen and other compounds
US10682357B2 (en) 2009-06-24 2020-06-16 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9675619B2 (en) 2009-06-24 2017-06-13 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US10172865B2 (en) 2009-06-24 2019-01-08 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9463158B2 (en) 2009-06-24 2016-10-11 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9737543B2 (en) 2009-06-24 2017-08-22 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9155701B2 (en) 2009-06-24 2015-10-13 Strategic Science & Technologies, Llc Delivery of ibuprofen and other compounds
US9492458B2 (en) 2009-06-24 2016-11-15 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9072659B2 (en) 2009-06-24 2015-07-07 Strategic Science & Technologies, Llc Topical composition containing naproxen
US10898489B2 (en) 2009-06-24 2021-01-26 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US11684624B2 (en) 2009-06-24 2023-06-27 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9161915B2 (en) 2009-06-24 2015-10-20 Strategic Science & Technologies, Llc Delivery of ibuprofen and other compounds
US8835382B2 (en) 2009-11-23 2014-09-16 Cubist Pharmaceuticals, Inc. Lipopeptide compositions and related methods
US9138456B2 (en) 2009-11-23 2015-09-22 Cubist Pharmaceuticals Llc Lipopeptide compositions and related methods
US9662397B2 (en) 2009-11-23 2017-05-30 Merck Sharp & Dohme Corp. Lipopeptide compositions and related methods
WO2011085015A3 (en) * 2010-01-06 2011-11-10 Elc Management Llc Skin lightening compositions
AU2013267022B2 (en) * 2010-01-06 2016-04-21 Elc Management Llc Skin lightening compositions
US8992897B2 (en) 2010-01-06 2015-03-31 Elc Management Llc Skin lightening compositions
US8722026B2 (en) 2010-01-06 2014-05-13 Elc Management, Llc Skin lightening compositions
US20110171149A1 (en) * 2010-01-06 2011-07-14 Yoko Niki Skin Lightening Compositions
KR101434073B1 (en) * 2010-01-06 2014-09-22 이엘씨 매니지먼트 엘엘씨 Skin lightening compositions
AU2015200590B2 (en) * 2010-01-06 2016-05-05 Elc Management Llc Skin lightening compositions
KR101584926B1 (en) * 2010-01-06 2016-01-13 이엘씨 매니지먼트 엘엘씨 Skin lightening compositions
CN102781419A (en) * 2010-01-06 2012-11-14 Elc管理有限责任公司 Skin lightening compositions
JP2013516474A (en) * 2010-01-06 2013-05-13 イーエルシー マネージメント エルエルシー Skin whitening composition
EP2521531A4 (en) * 2010-01-06 2016-02-17 Elc Man Llc Skin lightening compositions
AU2011203631B2 (en) * 2010-01-06 2013-12-19 Elc Management Llc Skin lightening compositions
US9314415B2 (en) 2010-01-06 2016-04-19 Elc Management Llc Skin lightening compositions
US9498442B2 (en) 2010-03-05 2016-11-22 Alfa Wassermann S.P.A. Rifaximin powder, process for preparing the same an controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect
US8513247B2 (en) 2010-03-26 2013-08-20 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US8916562B2 (en) 2010-03-26 2014-12-23 Galderma Research & Development Snc Methods and compositions for safe and effective treatment of telangiectasia
US8513249B2 (en) 2010-03-26 2013-08-20 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US9861632B2 (en) 2010-03-26 2018-01-09 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US9861631B2 (en) 2010-03-26 2018-01-09 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
US8163725B1 (en) 2010-10-21 2012-04-24 Galderma R&D SNC Gel compositions and methods of use
US8053427B1 (en) 2010-10-21 2011-11-08 Galderma R&D SNC Brimonidine gel composition
US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use
US9289495B2 (en) 2010-12-29 2016-03-22 Strategic Science & Technologies, Llc Systems and methods for treatment of allergies and other indications
US9498482B2 (en) 2010-12-29 2016-11-22 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US9833456B2 (en) 2010-12-29 2017-12-05 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US10258610B2 (en) 2011-07-29 2019-04-16 Alfasigma S.P.A. Pharmaceutical compositions comprising rifaximin, processes for their preparation and their use in the treatment of vaginal infections
US20140350049A1 (en) * 2011-11-29 2014-11-27 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for the treatment of darier disease
WO2013187891A1 (en) * 2012-06-13 2013-12-19 Alain Martin Method for treating a pulmonary disease state in mammals by up regulating indigenous in vivo levels of inflammatory agents in mammalian cells
WO2014006576A1 (en) * 2012-07-06 2014-01-09 Alfa Wassermann S.P.A. Pharmaceutical compositions comprising rifaximin and amino acids, preparation method and use thereof
ITBO20120368A1 (en) * 2012-07-06 2014-01-07 Alfa Wassermann Spa COMPOSITIONS INCLUDING RIFAXIMINA AND AMINO ACIDS, RIFAXIMINE CRYSTALS DERIVING FROM SUCH COMPOSITIONS AND THEIR USE.
EA028769B1 (en) * 2012-07-06 2017-12-29 Альфа Вассерманн С.П.А. Pharmaceutical compositions comprising rifaximin and amino acids, preparation method and use thereof
US9452157B2 (en) 2012-07-06 2016-09-27 Alfa Wassermann S.P.A Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof
US11547676B2 (en) 2012-12-28 2023-01-10 Teikoku Seiyaku Co., Ltd. Extended buprenorphine transdermal delivery compositions and methods for using the same
WO2014105480A1 (en) * 2012-12-28 2014-07-03 Teikoku Pharma Usa, Inc. Extended buprenorphine transdermal delivery compositions and methods for using the same
WO2014152382A1 (en) * 2013-03-15 2014-09-25 Strategic Science & Technologies, Llc Transdermal delivery of sildenafil and other phosphodiesterase type 5 inhibitors
CN105307635A (en) * 2013-03-15 2016-02-03 战略科学与技术有限责任公司 Transdermal delivery of sildenafil and other phosphodiesterase type 5 inhibitors
WO2014172344A1 (en) * 2013-04-16 2014-10-23 Alpha To Omega Pharmaceutical Consultants, Inc. Pharmaceutical compositions
US10123966B2 (en) 2013-05-16 2018-11-13 The Procter And Gamble Company Hair thickening compositions and methods of use
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
CN104095766A (en) * 2014-07-14 2014-10-15 拉芳家化股份有限公司 Sophorolipid-enhanced anti-dandruff composition and application thereof
CN104784185A (en) * 2015-04-03 2015-07-22 北京太禾利和医药科技有限公司 Nevirapine drug composition and preparation method thereof
US20180200289A1 (en) * 2015-07-02 2018-07-19 Veloce Biopharma, Llc Novel ophthalmic composition and methods of use
US20170000819A1 (en) * 2015-07-02 2017-01-05 Veloce Biopharma, Llc Novel ophthalmic composition and methods of use
US9770466B2 (en) * 2015-07-02 2017-09-26 Veloce Biopharma, Llc Ophthalmic composition and methods of use
US10398725B2 (en) 2015-07-02 2019-09-03 Veloce Biopharma, Llc Ophthalmic compositions and methods of use
WO2017007910A1 (en) 2015-07-09 2017-01-12 Galderma S.A. Method of reducing hair loss associated with chemotherapy
EP3319607A4 (en) * 2015-07-09 2019-04-03 Galderma S.A. Method of reducing hair loss associated with chemotherapy
US10828308B2 (en) 2015-10-16 2020-11-10 Hadasit Medical Research Services And Development Ltd. Treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis with delayed-release 6-mercaptopurine
WO2017161136A1 (en) * 2016-03-18 2017-09-21 Oak Crest Institute Of Science Acid salts for vaginal drug delivery
CN107349207A (en) * 2016-05-10 2017-11-17 刘民祥 It is a kind of except the medicine of acne
JP2019535795A (en) * 2016-11-28 2019-12-12 セリックス バイオ プライヴェート リミテッドCellix Bio Private Limited Compositions and methods for the treatment of oral infections
US11485730B2 (en) 2016-11-28 2022-11-01 Cellix Bio Private Limited Compositions and methods for the treatment of fungal infections
JP7176760B2 (en) 2016-11-28 2022-11-22 セリックス バイオ プライヴェート リミテッド Compositions and methods for the treatment of fungal infections
JP2019081747A (en) * 2017-10-30 2019-05-30 株式会社 資生堂 Hair treatment agent
CN110604730A (en) * 2018-06-15 2019-12-24 镇学初 Application of metformin salt in treatment of cerebral infarction

Also Published As

Publication number Publication date
WO2006084174A2 (en) 2006-08-10
WO2006084174A3 (en) 2007-10-04

Similar Documents

Publication Publication Date Title
US20050196418A1 (en) Bioavailability and improved delivery of alkaline pharmaceutical drugs
US20080032937A1 (en) Bioavailability and Improved Delivery of Alkaline Pharmaceutical Drugs
AU2018229508B2 (en) Pharmaceutical cream compositions comprising oxymetazoline
US20080113037A1 (en) Topical Compositions Comprising Polyhydroxy Acids and/or Lactones for Improved Cutaneous Effects of Oxidative Therapeutic Drugs
US20180021247A1 (en) Topical compositions comprising hydroxy acids and cannabinoids for skin care
US20060251597A1 (en) Anti-odor compositions and therapeutic use
AU734741B2 (en) Molecular complex and control-release of alpha hydroxyacids
US20060211754A1 (en) Compositions comprising N-propanoyl derivatives of amino acids, aminocarbohydrates and derivatives thereof
US20040033963A1 (en) Urea composition
US7709014B2 (en) Hydroxy-oligocarboxylic esters: effects on nerve and use for cutaneous and mucocutaneous organs or sites
AU2004222305A1 (en) Improved bioavailability and improved delivery of acidic pharmaceutical drugs
US20040220259A1 (en) Topical treatment of dermatological disorders associated with reactive or dilated blood vessels
JP2000186036A (en) Chemical peeling agent composition

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION